Asymmetric shunt for redistributing atrial blood volume

ABSTRACT

An asymmetric device for regulating blood volume distribution across a patient&#39;s atrial septum having a first expandable end region and a second expandable end region. The first expandable end region is transitionable from a contracted delivery state to an expanded deployed state in which the first expandable end region extends into the patient&#39;s left atrium and an inlet end of the first expandable end region is in a first plane. The second expandable end region is transitionable from a contracted delivery state to an expanded deployed state in which the second expandable end region extends into the patient&#39;s right atrium and an outlet end of the second expandable end region is in a second plane, such that the first plane intersects the second plane. The device further includes a neck region joining the first expandable end region to the second expandable end region, wherein the neck region is sized and shaped for placement in the patient&#39;s atrial septum.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/408,419, filed May 9, 2019, now U.S. Pat. No.11,291,807, which is a continuation-in-part application of U.S. patentapplication Ser. No. 16/130,988, filed Sep. 13, 2018, now U.S. Pat. No.10,925,706, which is a continuation of U.S. patent application Ser. No.15/449,834, filed Mar. 3, 2017, now U.S. Pat. No. 10,076,403, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

This application generally relates to percutaneously placed asymmetricimplants and methods for redistributing blood from one cardiac chamberto another to address pathologies such as heart failure (“HF”),myocardial infarction (“MI”) and pulmonary arterial hypertension(“PAH”).

BACKGROUND OF THE INVENTION

Heart failure is the physiological state in which cardiac output isinsufficient to meet the needs of the body or to do so only at a higherfiling pressure. There are many underlying causes of HF, includingmyocardial infarction, coronary artery disease, valvular disease,hypertension, and myocarditis. Chronic heart failure is associated withneurohormonal activation and alterations in autonomic control. Althoughthese compensatory neurohormonal mechanisms provide valuable support forthe heart under normal physiological circumstances, they also play afundamental role in the development and subsequent progression of HF.

For example, one of the body's main compensatory mechanisms for reducedblood flow in HF is to increase the amount of salt and water retained bythe kidneys. Retaining salt and water, instead of excreting it viaurine, increases the volume of blood in the bloodstream and helps tomaintain blood pressure. However, the larger volumes of blood also causethe heart muscle, particularly the ventricles, to become enlarged. Asthe heart chambers become enlarged, the wall thickness decreases and theheart's contractions weaken, causing a downward spiral in cardiacfunction. Another compensatory mechanism is vasoconstriction of thearterial system, which raises the blood pressure to help maintainadequate perfusion, thus increasing the load that the heart must pumpagainst.

In low ejection fraction (“EF”) heart failure, high pressures in theheart result from the body's attempt to maintain the high pressuresneeded for adequate peripheral perfusion. However, as the heart weakensas a result of such high pressures, the disorder becomes exacerbated.Pressure in the left atrium may exceed 25 mmHg, at which stage, fluidsfrom the blood flowing through the pulmonary circulatory systemtransudate or flow out of the pulmonary capillaries into the pulmonaryinterstitial spaces and into the alveoli, causing lung congestion and ifuntreated the syndrome of acute pulmonary edema and death.

Table 1 lists typical ranges of right atrial pressure (“RAP”), rightventricular pressure (“RVP”), left atrial pressure (“LAP”), leftventricular pressure (“LVP”), cardiac output (“CO”), and stroke volume(“SV”) for a normal heart and for a heart suffering from HF. In a normalheart beating at around 70 beats/minute, the stroke volume needed tomaintain normal cardiac output is about 60 to 100 milliliters. When thepreload, after-load, and contractility of the heart are normal, thepressures required to achieve normal cardiac output are listed inTable 1. In a heart suffering from HF, the hemodynamic parameters change(as shown in Table 1) to maintain peripheral perfusion.

TABLE 1 Parameter Normal Range HF Range RAP (mmHg) 2-6  6-20 RVSP (mmHg)15-25  20-80 LAP (mmHg) 6-12 15-50 LVEDP (mmHg) 6-12 15-50 CO(liters/minute) 4-8  2-6 SV (milliliters/beat) 60-100 30-80

HF is generally classified as either systolic heart failure (“SHF”) ordiastolic heart failure (“DHF”). In SHF, the pumping action of the heartis reduced or weakened. A common clinical measurement is the ejectionfraction, which is a function of the blood ejected out of the leftventricle (stroke volume) divided by the maximum volume in the leftventricle at the end of diastole or relaxation phase. A normal ejectionfraction is greater than 50%. Systolic heart failure generally causes adecreased ejection fraction of less than 40%. Such patients have heartfailure with reduced ejection fraction (“HFrEF”). A patient with HFrEFmay usually have a larger left ventricle because of a phenomenon called“cardiac remodeling” that occurs secondarily to the higher ventricularpressures.

In DHF, the heart generally contracts normally, with a normal ejectionfraction, but is stiffer, or less compliant, than a healthy heart wouldbe when relaxing and filling with blood. Such patients are said to haveheart failure with preserved ejection fraction (“HFpEF”). This stiffnessmay impede blood from filling the heart and produce backup into thelungs, which may result in pulmonary venous hypertension and lung edema.HFpEF is more common in patients older than 75 years, especially inwomen with high blood pressure.

Both variants of HF have been treated using pharmacological approaches,which typically involve the use of vasodilators for reducing theworkload of the heart by reducing systemic vascular resistance, as wellas diuretics, which inhibit fluid accumulation and edema formation, andreduce cardiac filling pressure. No pharmacological therapies have beenshown to improve morbidity or mortality in HFpEF whereas several classesof drugs have made an important impact on the management of patientswith HFrEF, including renin-angiotensin antagonists, beta blockers, andmineralocorticoid antagonists. Nonetheless, in general, HF remains aprogressive disease and most patients have deteriorating cardiacfunction and symptoms over time. In the U.S., there are over 1 millionhospitalizations annually for acutely worsening HF and mortality ishigher than for most forms of cancer.

In more severe cases of HFrEF, assist devices such as mechanical pumpsare used to reduce the load on the heart by performing all or part ofthe pumping function normally done by the heart. Chronic leftventricular assist devices (“LVAD”), and cardiac transplantation, oftenare used as measures of last resort. However, such assist devicestypically are intended to improve the pumping capacity of the heart, toincrease cardiac output to levels compatible with normal life, and tosustain the patient until a donor heart for transplantation becomesavailable. Such mechanical devices enable propulsion of significantvolumes of blood (liters/min), but are limited by a need for a powersupply, relatively large pumps, and pose a risk of hemolysis, thrombusformation, and infection. Temporary assist devices, intra-aorticballoons, and pacing devices have also been used.

Various devices have been developed using stents to modify bloodpressure and flow within a given vessel, or between chambers of theheart. For example, U.S. Pat. No. 6,120,534 to Ruiz is directed to anendoluminal stent for regulating the flow of fluids through a bodyvessel or organ, for example, for regulating blood flow through thepulmonary artery to treat congenital heart defects. The stent mayinclude an expandable mesh having lobed or conical portions joined by aconstricted region, which limits flow through the stent. The mesh maycomprise longitudinal struts connected by transverse sinusoidal orserpentine connecting members. Ruiz is silent on the treatment of HF orthe reduction of left atrial pressure.

U.S. Pat. No. 6,468,303 to Amplatz et al. describes a collapsiblemedical device and associated method for shunting selected organs andvessels. Amplatz describes that the device may be suitable to shunt aseptal defect of a patient's heart, for example, by creating a shunt inthe atrial septum of a neonate with hypoplastic left heart syndrome(“HLHS”). That patent also describes that increasing mixing of pulmonaryand systemic venous blood improves oxygen saturation, and that the shuntmay later be closed with an occluding device. Amplatz is silent on thetreatment of HF or the reduction of left atrial pressure, as well as onmeans for regulating the rate of blood flow through the device.

Implantable interatrial shunt devices have been successfully used inpatients with severe symptomatic heart failure. By diverting or shuntingblood from the left atrium (“LA”) to the right atrium (“RA”), thepressure in the left atrium is lowered or prevented from elevating ashigh as it would otherwise (left atrial decompression). Such anaccomplishment would be expected to prevent, relieve, or limit thesymptoms, signs, and syndromes associated with pulmonary congestion.These include severe shortness of breath, pulmonary edema, hypoxia, theneed for acute hospitalization, mechanical ventilation, and death.

Shunt flow is generally governed by the pressure gradient between theatria, and by the fluid mechanical properties of the shunt device. Thelatter are typically affected by the shunt's geometry and materialcomposition. For example, the general flow properties of similar shuntdesigns have been shown to be related to the mean interatrial pressuregradient and the effective orifice diameter.

Percutaneous implantation of interatrial shunts generally requirestransseptal catheterization immediately preceding shunt deviceinsertion. The transseptal catheterization system is placed, from anentrance site in the femoral vein, across the interatrial septum in theregion of fossa ovalis (“FO”), which is the central and thinnest regionof the interatrial septum. This is the same general location where acongenital secundum atrial septal defect (“ASD”) would be located. TheFO in adults is typically 15-20 mm in its major axis dimension and ≤3 mmin thickness, but in certain circumstances may be up to 10 mm thick. LAchamber access may be achieved using a host of different techniquesfamiliar to those skilled in the art, including but not limited to:needle puncture, stylet puncture, screw needle puncture, andradiofrequency ablation. The passageway between the two atria is dilatedto facilitate passage of a shunt device having a desired orifice size.Dilation generally is accomplished by advancing a tapered sheath/dilatorcatheter system or inflation of an angioplasty-type balloon across theFO.

U.S. Patent Publication No. 2005/0165344 to Dobak, III describesapparatus for treating heart failure that includes a tubular conduithaving an emboli filter or valve, the device configured to be positionedin an opening in the atrial septum of the heart to allow flow from theleft atrium into the right atrium. Dobak discloses that shunting ofblood may reduce left atrial pressures, thereby preventing pulmonaryedema and progressive left ventricular dysfunction, and reducing LVEDP.Dobak describes that the device may include deployable retention struts,such as metallic arms that exert a slight force on the atrial septum onboth sides and pinch or clamp the device to the septum.

Two types of percutaneously implantable shunts have been described inthe medical and patent literature. In short-term, small-size clinicaltrials, both types have been shown to be associated with improvements insymptoms, quality of life measurements, and exercise capacity. Bothshunts also have observed and theoretical drawbacks, which may limittheir effectiveness and use.

The first type of shunt is henceforth referred to as an orifice-platemesh shunt. Orifice-plate mesh shunts comprise a metallic mesh thatwraps around both sides of the septum with a hole in the center, andanatomically mimics the location and geometrical characteristics of asmall congenital secundum ASD. The shunt geometry generally resembles athin plate with a hole in it. In most embodiments, the “plate” comprisesboth mesh material and atrial septal tissue encased by the mesh. Oneexample of such devices, designed by Corvia Medical, Inc., TewksburyMass., consists of a self-expanding nitinol mesh that forms a pair ofdisc-like flanges with an open orifice in the center. The maximaldiameter of the discs is 19.4 mm and the orifice diameter is 8 mm. Eachdisc flange has multiple truss-like legs that deploy into a presetconfiguration that wraps around the LA and RA sides of the interatrialseptum and applies a clamping force to the tissue.

Another example of such a mesh type device, developed by OcclutechInternational AB, Helsingborg, Sweden, resembles a dual-disc occluderused for closing congenital secundum ASDs, which additionally includes ashort open barrel orifice in the center that connects the two discs.

A major benefit of the foregoing orifice-plate mesh shunts over othershunt designs is simplicity of manufacture. Although relatively simplein theory and construction, orifice-plate mesh type shunts have severalimportant drawbacks that are expected to reduce their overall potentialfor clinical safety and effectiveness.

A first drawback of orifice-plate devices is the susceptibility tonarrow or close during the post-implantation healing period. Forexample, neoendocardial tissue ingrowth, referred to as pannus, growsfrom the underlining tissue to cover the mesh and narrow or partiallyocclude the shunt orifice. During the period following implantation,local trauma caused by crossing and dilating the FO, plus the chroniceffects of continuous pressure applied by the mesh material on theseptal tissue, provoke a localized healing response. This responseentails activation of an inflammatory process, attracting lymphocytesand macrophages to the area of tissue injury. These inflammatory cellsin turn release a variety of cytokines that signal fibroblasts andsmooth-muscle cells from the wound margins to dedifferentiate, migrate,proliferate and encapsulate affected portions of the implanted device.The fibroblasts and smooth muscle cells then secrete extracellularmatrix material composed of collagen and proteoglycans, whichextracellular matrix forms the bulk of the pannus. The duration of thishealing phase in humans is typically up to 6-9 months, but may be longerif there is a chronic source for tissue injury such as devicecompression or erosion of adjacent tissue. Eventually this pannus iscovered with neoendothelial cells, causing the pannus growth to stop orstabilize. In the long term, the collagen of the pannus remodels, butgenerally retains its space occupying properties. Such tissue ingrowthtypically spreads over the surfaces of the implant's struts, mesh, ordiscs, and may substantially narrow the orifice lumen or even entirelyocclude the shunt. Narrowing or occlusion of the shunt prevents LAdecompression and limits any positive effect for the patient.

The degree of luminal narrowing may be quite variable between patientsdue to differences in the severity of local injury—the more injury, themore exaggerated the pannus formation. Also, variability results fromdifferences in host wound healing responses. For example, the amount andcharacter of extracellular matrix may affect the duration of healing andamount of material deposited. Thus, for an orifice-plate mesh shunt, theeventual orifice lumen size will be highly variable. These processeswill be familiar to one skill in the art as it is generally analogous tothe type of late lumen loss that occurs in arteries when bare metalstents are used to treat atherosclerotic stenosis.

In a trial described in the publication, “A Transcatheter IntracardiacShunt Device for Heart Failure with Preserved Ejection Fraction (REDUCELAP-HF): A Multicentre, Open-label, Single-arm, Phase 1 Trial” byHasenfuss, et al., 14 of 64 patients implanted with an orifice-platemesh shunt device had no demonstrable flow across the shunt ontransthoracic echocardiographic Doppler imaging at 6 months afterimplantation. It was not reported whether the shunts were occluded or ifthe imaging study was simply too technically difficult to tell forcertain. Although additional interventional cardiology procedures may beundertaken to restore lost luminal patency, such procedures may poseunacceptable risks, including death and stroke from embolization of theorifice-clogging material, and there is no guarantee that the orificewill not occlude again.

A second drawback of an orifice-plate mesh shunt is the potential forparadoxical embolization. Paradoxical embolization refers to an arterialthromboembolism originating in the venous vasculature (venousthromboembolism or “VTE”), such that an embolus traverses right-to-leftthrough a cardiac shunt into the systemic arterial circulation. The mostsevere complication of paradoxical embolization occurs when an emboluslodges in the cerebral circulation with resulting cerebral infarction(stroke). Similarly, if a paradoxical embolus enters the coronaryarterial circulation, myocardial infarction (“MI”) may ensue. Otherembolic syndromes result from embolization to the mesenteric, renal, andperipheral arteries supplying the limbs. These may cause, respectively,ischemic bowel syndrome, hematuria with worsening renal function, andgangrene requiring amputation.

Most frequently, VTE in adults is the consequence of in situ thrombosisin the deep veins (deep venous thrombosis or “DVT”) of the lowerextremities or pelvis. For the most part, clinically relevant venousemboli develop in the popliteal veins or more proximally in larger veinsof the upper thigh or pelvis. In patients with DVT involving thepopliteal vein, the venous diameter averaged 11.4 mm (range from 6.2 mmto 20.1 mm). Often, emboli are described as having the form of a cast ofthe vein's lumen with a width equal to the diameter of the vein oforigin. These thrombi also tend to be elongated, corresponding to thelength of the occluded venous segment.

The risk factors associated with thromboembolic disease include avariety of anatomic, physiological, rheological variables and diseasestates. Heart failure is a well-recognized risk factor for DVT and VTE,especially in patients with reduced left ventricular systolic function.About 3% of deaths in heart failure patients are due to VTE, usuallyassociated with pulmonary embolism. Patients with transvenousendocardial pacing leads and an intracardiac shunt have a 3-foldincreased risk of systemic thromboembolism, suggesting that paradoxicalembolism is a contributing underlying cause. There is evidence that therisk of paradoxical embolism is directly related to the orifice size ofnaturally occurring atrial level shunts such as ASD and patent foramenovale (“PFO”). The presence of an atrial septal aneurysm is anadditional risk factor. For example, as described in the publication“Transcatheter Amplatzer Device Closure of Atrial Septal Defect andPatent Foramen Ovale in Patients with Presumed Paradoxical Embolism” byKhositsth, et al., in a series of 103 adult patients with paradoxicalembolization, an ASD was present in 12%, whereas PFO was present in 81%.In patients with clinically significant ASD referred for closure, theincidence of paradoxical embolus has been reported to be up to 14%.

It has been asserted that in order for VTE to enter the systemiccirculation, the prevailing LA to RA pressure gradient must betemporarily reduced, eliminated or reversed so that blood will eitherflow slowly across the shunt, cease to flow across the shunt or flowretrograde across the shunt. Echo/Doppler imaging studies often revealsome amount of shunting in both directions (bi-directional shunting) inpatients with congenital ASD, even when LA to RA flow predominates.Bidirectional shunting may be best demonstrated when a subject performsa Valsalva maneuver (straining caused by exhalation against a closedglottis). Valsalva increases intrathoracic pressure, which causes the RAand LA pressures to equalize after several seconds and then for the RApressure to transiently exceed LA pressure on exhalation. Intermittentbidirectional flow also may be observed at rest when the interatrialpressure gradient is low, or intermittently during the cardiac cyclewhen LA contraction is delayed compared to RA contraction (interatrialconduction delay). This is seen especially when the atria are enlargedor diseased, such as in heart failure. In this setting, interatrialelectrical conduction delay results in retardation of LA contraction.Bidirectional shunting can also be seen transiently during inspiration,when venous return to the RA is increased, during coughing, withabdominal compression, during forced exhalation, or in the presence ofsevere tricuspid valve regurgitation. Chronically increased pulmonaryarterial pressure, as seen in severe pulmonary hypertension, whetherprimary or secondary to chronic lung disease, recurrent pulmonaryembolism, or due to chronic right ventricular volume overload, has beenassociated with chronic and more severe RA to LA shunting.

Additional phenomena associated with RA to LA shunting are diminishedpulmonary blood flow and decreased arterial oxygen saturation due tosystemic venous admixing. When these findings are also transient, theyare generally well tolerated. Thus, prevention of significant or largerparadoxical emboli is the primary concern rather than preventing reverseshunting per se. As the consequences of paradoxical embolization can becatastrophic, it is desirable, particularly in high-risk patients, thatan implantable shunt be equipped with mechanism(s) that limit orminimize the chances of paradoxical embolization or minimize the chancesof transporting large emboli.

From these data, it seems reasonable to expect that an orifice-platemesh shunt, by virtue of its anatomic similarities with congenitalsecundum ASD, would have a similar risk of paradoxical embolization. Itis easily understandable that a thin plate-orifice mesh type ofartificial shunt might be more susceptible to paradoxical embolizationthan other types of shunts with longer orifice geometries, e.g., anozzle. For any given quanta of RA volume (blood or thrombus), thestatistical likelihood of traversing retrograde across the shunt andinto the LA would be expected to be a complex function of the durationof pressure gradient reversal, flow patterns in the RA, shunt tunneldistance affecting the length of the flow velocity streamlines, and flowvelocity and orifice or lumen size.

A third drawback of an orifice-plate mesh shunt is that percutaneousremoval of the shunt is only possible at the time of implantation.Should the shunt become a nidus for infection, develop fatigue orcorrosion fractures of its metallic framework, or erode or otherwiseimpinge on other vital cardiac structures, it cannot be removed bypercutaneous retrieval/removal techniques. This is because the shunt,with its large “footprint” on the interatrial septum, is encased inpannus tissue. Attempts at percutaneous removal may result in tearing ofthe septum, pericardial tamponade, and device embolization into thesystemic circulation, resulting in death or the need for emergencysurgery. Safe removal would require performing open heart surgery. Thisentails that the heart be bypassed using an extracorporeal membrane pumpoxygenator (cardiopulmonary bypass), so the heart can be opened, theshunt removed, and the septum repaired. Performing such surgicalprocedures in patients with already established severe heart failure,including its frequently associated co-morbid conditions such asperipheral, cerebrovascular, and coronary artery disease, renaldysfunction, and diabetes, would be expected to have substantial risksfor mortality or severe morbidity.

A fourth drawback of an orifice-plate mesh type of shunt is that itsgeometry renders it relatively inefficient in supporting high flow. Forany given pressure gradient across the shunt, an orifice-plate geometryrequires a larger orifice because it has a reduced effective orificesize compared with other geometries, such as a venturi-shaped lumen, ora conical shaped nozzle. This is because with an office-plate, there ismore energy loss associated with eddy currents at the edges of theplate. Orifice-plate geometries may be categorized as having arelatively low discharge coefficient, which is a dimensionlessfluid-mechanical parameter that relates to the relationship between flowand actual orifice size. For practical purposes, the dischargecoefficient is the ratio of areas of the exiting jet vena contracta,which is the narrowest portion of the jet, compared to the shuntorifice. For example, the coefficient of discharge for orifice platesplaced in pipes tends to be approximately 0.6, but rarely exceeds 0.65.The discharge coefficient is affected by the orifice and chamberdimensions, the pressure gradient, and the viscosity of blood and/or theReynolds number of the specific flow condition. This differs from themore efficient passage of flow through a classic venturi type ofnarrowing, where the discharge coefficient usually exceeds 0.9 and istypically in the range of 0.94 to 0.98. The result is that, incomparison with more efficient shunt lumen geometries, an orifice-platemesh shunt requires a larger orifice diameter to accommodate the sameamount of flow for any given pressure differential across the shunt.

A fifth drawback of an orifice-plate mesh shunt is that it occupies alarge area or footprint on the interatrial septum. The flanges of thedevice that anchor the shunt typically occupy the entire area of thefossa ovalis and may overlap adjoining muscular portions of theinteratrial septum. These flanges exert persistent pressure on theseptum, causing injuring and stimulating an exaggerated healing responseas described above. Also, the rigidity of the mesh may interfere withthe normal motion of the muscular septum. The flanges additionally mayimpinge on adjacent cardiac structures such as the roof of the leftatrium, the ostia of the pulmonary veins, and the aorta root and sinusesof Valsalva, where due to chronic rubbing contact or sandwichingcompressive forces, they may erode into these vital structures. Sucherosion has been associated with severe complications including cardiactamponade and death. For example, the similarly sized Amplatzer ASD discocclusion device described above has been occasionally associated witherosion into adjoining tissues with resulting catastrophic outcomes.

Additional issues associated with placing relatively large devices withcomplex three-dimensional geometries are potential difficulties inpositioning the shunts accurately in the FO, obtaining sufficient tissueanchoring to prevent migration, and having devices conform toirregularities of the cardiac anatomy. For example, in a report ofattempted implantation of orifice-plate mesh shunts in 66 patients inthe above cited publication authored by Hasenfuss, et al., deviceplacement was not possible in two patients. And of the 64 implantedpatients, the device had to be removed and re-implanted in another 3patients due to misplacement, migration, or embolization of the firstattempted implant.

Finally, the large footprint on the atrial septum may hinder or renderimpossible performing other interventional procedures that requiretransseptal access. The large flange diameter and small mesh pore sizesgenerally make catheter crossing of the atrial septum possible onlythrough the central shunt orifice itself. Transseptal procedures usingsmall diameter catheters, such as atrial fibrillation RF ablation, maybe conducted through the orifice-plate lumen only if it is notobstructed by pannus and the orifice location permits entry into allfour pulmonary veins. Other structural heart disease procedures thathave large diameter delivery systems and/or require crossing the FO inspecific locations may encounter difficulties or simply not be possible.These procedures include left atrial appendage occlusion, mitral valveedge-to-edge (“MitraClip”) repair, and transvascular mitral valvereplacement. For example, placing of a MitraClip optimally requirescrossing the FO in its superior-posterior quadrant. The guiding catheterhas a tip inner diameter of 7.7 mm (23 Fr). Similar transseptal accessis needed to perform reconstructive mitral annuloplasty with theCardioband device marketed by Valtech. In these cases, the onlyalternatives might be higher risk therapeutic approaches involvingtrans-left ventricular apical access or open heart surgery.

The second type of shunt is referred to as a valved unidirectionalshunt. These shunts attempt to overcome some of the drawbacks oforifice-plate devices. For example, valved unidirectional shunts haveembodiments containing a one-way or check-valve to limit reverseshunting and paradoxical embolization. Some of the valve configurationsare designed to open when the LA-RA pressure gradient exceeds apredefined threshold. Other valve configurations close only when the RApressure exceeds LA pressure (reversed gradient).

U.S. Pat. No. 9,034,034 to Nitzan, the entire contents of which areincorporated by reference herein, solves many of the drawbacks ofplate-like orifice mesh shunts describe above. An embodiment of theNitzan-type shunt comprises an hourglass or diabolo outer shape, havinga small FO footprint minimizing septal injury, which is expected tominimize pannus growth and obliteration of the shunt lumen. Its one-wayvalve also is designed to reduce the potential for reverse shunting andparadoxical embolization. The relatively small footprint of the shunt incontact with the septum and encapsulated collapsible nitinol frame isdesigned to facilitate percutaneous extraction from the septum andretrieval from the body using a standard goose-neck snare and large-boresheath, thus making the device more easily retrieved. The venturitube-like inner lumen of the diabolo shape provides better bulk flowcharacteristics, permitting a smaller orifice for the same amount offlow compared to orifice-plate shunts. And finally, the small footprinton the FO and the hourglass shape are designed to facilitate accurateplacement and retention during implantation. This geometry alsominimizes interference with normal motion of the interatrial septum, andthe small footprint provides space surrounding the shunt for otherpotential interventional procedures that require transseptalcatheterization.

One embodiment of the Nitzan design, manufactured by V-Wave, Ltd(Caesarea, Israel), designed to support unidirectional left-to-rightflow, comprises a self-expanding frame constructed from a laser-cutnitinol tube. The frame includes five sinusoidal circumferential strutsinterconnected by six longitudinal bars. The frame is heat-set so thatit has an asymmetrical hourglass shape or a diabolo shape. The shunt isdeployed so that the neck (5.3 mm outer diameter) is placed across theFO and secured in place by its external surface geometry. The shunt'swidest portion has a conical shape with an approximately 14.3 mm outerdiameter at the LA end of the shunt, which serves as an “entry” port onthe distal end of the entry funnel. The entry funnel is deployed in theleft atrium, and registers the neck of the shunt to the region of theFO. A second, slightly narrower bell-shaped portion forms the exitportion of the shunt, which expands to a maximum outer diameter of 11.4mm at the RA end of the shunt. The shunt does not require flanges,discs, or tissue anchors to secure it in place. Septal retention isachieved without applying persistent pressure, tension or rubbingcontact on the tissue adjoining the device neck.

The V-Wave shunt has a single inner lumen where flow is entrained intothe entry funnel in the LA and passes through the constricted neckhaving a 5.1 mm inner diameter, which resembles a venturi-type orifice,and then exits through a bioprosthetic valve positioned near the RA endof the shunt. The entry funnel and the central neck region areencapsulated with expanded polytetrafluoroethylene (“ePTFE”) to form askirt or cover over the frame. The skirt is designed to facilitatelaminar flow and limit pannus ingrowth during device healing. The exitbell-shaped portion contains three, glutaraldehyde-fixed, porcinepericardial leaflets sutured to the frame at the right atrial extent ofthe ePTFE encapsulation. The leaflets are designed to create a smoothexit channel and remain in the open position, closing only when the RApressure exceeds LA pressure by 1-2 mmHg, thus preventing reverseright-to-left shunting.

For deployment, the V-Wave shunt is compressed in a loading tube whereit is attached to a triple-latch cable delivery catheter. The loadingtube is inserted into a 14F delivery sheath that has been previouslyplaced after a transseptal catheterization from the right femoral veinacross the FO. The shunt then is advanced through the sheath until theentry funnel has been deployed in the LA. The entire system is withdrawnas a unit until the LA funnel is in contact with the left side of theFO. The delivery catheter latches are unhooked from the shunt, thedelivery catheter withdrawn so the right atrial side of the shunt isheld only by its radial force against the delivery sheath. Then thedelivery sheath is withdrawn, thereby deploying the exit bell-shapedportion of the shunt on the RA side of the FO. Device placement may beguided and confirmed by fluoroscopy and echocardiography, e.g.,intracardiac echo or transesophageal echo.

Pre-clinical testing on the V-Wave shunt was performed in an establishedjuvenile ovine (sheep) model that created an ischemic cardiomyopathyform of heart failure. The sheep were pre-treated with sequentialcoronary artery microembolization as described in the publication,“Chronic Heart Failure Induced by Multiple Sequential CoronaryMicroembolization in Sheep” by Schmitto et al. After several weeks, thesheep manifested evidence of severe left ventricular systolicdysfunction and develop elevated LV, LA, and pulmonary artery pressures.In a 12-week survival study, this V-Wave shunt was associated withsignificant improvements in LA pressure and left ventricular ejectionfraction. All manifestations of worsening heart failure were improvedand in some cases reversed with interatrial shunting. Concurrent controlanimals with established heart failure, but were not implanted with theV-Wave shunt, demonstrated progressive worsening of LV ejectionfraction, and intracardiac/pulmonary pressure during 3-month follow-up.The physiological improvements in shunted animals were substantial eventhough the shunt volume was assessed to be small. The pulmonary bloodflow/systemic blood flow ratio (Qp/Qs) was between 1.1 to 1.2, asmeasured by oximetry, which is consistent with a very small shunt.Naturally occurring ASDs, with a Qp/Qs less than 1.5, are generally leftuntreated as they are well tolerated for decades by the compliant rightheart and pulmonary vasculature, without evidence of worsening rightventricular failure despite mild chronic volume overload. This wasconfirmed in the sheep model where RA and pulmonary artery pressuresdecreased to baseline levels with shunting, but progressively worsenedin the control animals.

A total of 38 patients were implanted with the V-Wave hourglass-shapedshunt having valve leaflets in two similar feasibility studies. Thebaseline characteristics of the combined study populations aresummarized in Table 1 below.

TABLE 1 Baseline characteristics of 38 patients implanted with valvedhourglass-shaped shunt device Age, years 66 ± 9  Male gender, % 92 Bodymass index, kg/m2 30 ± 6  NYHA class, median III (97%), IV (3%) IschemicCardiomyopathy, % 76 DM/HTN/AFIB, % 68/84/53 ACEi-ARB/BB/MRA/DIUR, %78/100/75/94 CRT-D or ICD/CRT-D or CRT-P, % 74/39 NT-proBNP, pg/ml 2640± 2301 eGFR, mL · min−1 · 1.73 m−2 54 ± 20 6 MWT, m 282 ± 114 PCWP, mmHg20 ± 6  RAP, mmHg 8 ± 4 PAP mean, mmHg 30 ± 7  CI, L · min−1 · m−2 2.1 ±0.5 PVR, mmHg/L · min−1 2.9 ± 1.4 LVEF (HFrEF, n = 30), % 26 ± 7  LVEF(HFpEF, n = 8), % 50 ± 9  NYHA = New York Heart Association heartfailure classification; DM = diabetes mellitus; HTN = hypertension; AFIB= atrial fibrillation; ACEi-ARB = receiving angiotensin convertingenzyme inhibitor or angiotensin receptor blocker; BB = receiving betablocker; MRA = receiving mineralocorticoid antagonist; DIUR = receivingloop diuretic; CRT-D = implanted with combination cardiacresynchronization therapy pacemaker with ICD; ICD = implantablecardioverter/defibrillator; CRT-P = implanted with cardiacresynchronization therapy pacemaker without combination ICD; NT-proBNP =N-terminal pro b-type natriuretic peptide; eGFR = estimated glomerularfiltration rate; 6 MWT = 6 minute walk test distance; PCWP = pulmonarycapillary wedge pressure; RAP = right atrial pressure; PAP = pulmonaryartery pressure; CI = cardiac index; PVR = pulmonary vascularresistance; LVEF = left ventricular ejection fraction; HFrEF = heartfailure with reduced ejection fraction; HFpEF = heart failure withpreserved ejection fraction.These parameters and abbreviations are well known to one skilled in theart.

All patients had New York Heart Association (“NYHA”) Class III orambulatory Class IV heart failure symptoms at the time of studyenrollment. Patients with either reduced or preserved left ventricularejection fraction were included. There was a high frequency ofco-morbidities known to be associated with a poorer prognosis includingcoronary artery disease, diabetes mellitus, atrial fibrillation, andchronic kidney dysfunction. All patients received appropriateguideline-driven medical and device therapies prior to study enrollment.Patients had evidence of elevated levels of natriuretic peptides,reduced exercise capacity, elevated intracardiac and pulmonary arterypressures, increased pulmonary vascular resistance, and reduced cardiacoutput. These factors have also been associated with poor outcomes.Patients were excluded if they had severe right ventricular dysfunctionor severe pulmonary hypertension.

Implantation of the V-Wave shunt was successful in all 38 patients andno device replacements were performed. Shunts remained implanted in theatrial septum without dislodgements, migrations or apparent interferencewith normal septal motion on fluoroscopic or echocardiographic imaging.No shunts have required removal or replacement for infection or strutfracture. Follow-up imaging studies show that there are adjacentlocations on the FO, that are available and amenable for performingtransseptal procedures to treat other cardiac conditions, including, forexample, atrial fibrillation ablation, left atrial appendage occlusion,and mitral valve repair. The valve apparatus, when functioning normally,has been shown to effectively prevent reverse (right-to-left) shunting.Echocardiographic contrast and Doppler studies during rest or Valsalvamaneuver show that there is no reverse shunting in the early monthsafter human implantation. Furthermore, no thromboembolic clinicalevents, including paradoxical embolization, have been observed duringthe first year of follow-up.

Shunt patency is defined as LA to RA flow through the shunt as observedduring transesophageal echo/Doppler study. At 3-months afterimplantation of the V-Wave shunts, patency was confirmed in allpatients. The pulmonary to systemic flow ratio (Qp/Qs), as measured byechocardiography, increased from 1.04±0.22 at baseline to 1.18±0.16shortly after implantation (p<0.03). In the subgroup of 30 patients withHFrEF presented by Dr. William Abraham, MD at TCT 2016 in WashingtonD.C., there were statistically significant (p<0.05) improvements inclinician-assessed symptoms, patient assessed quality-of-life scores,and exercise capacity as measured by a 6-minute hall walk testing at 3,6, and 12 months following implantation There was no deterioration innatriuretic hormone levels, echocardiographic, or hemodynamicparameters. Most importantly, the annualized (Poisson) heart failurehospitalization rate with shunting (0.17 heart failure hospitalizationper patient year), was substantially reduced in comparison to a wellmatched historical control groups (CHAMPION trial Control and Treatmentgroups, 0.90 and 0.67 heart failure hospitalization per patient year,respectively). These data provide adequate proof-of-concept thatinteratrial shunting is of benefit to patients with severe symptomaticheart failure. Moreover, these data strongly support moving forward withlarger-scale clinical trials including randomized clinical trials.

Notwithstanding the initial success observed in the foregoing trial,device occlusion, e.g., shunts having undetectable LA to RA flow, wasobserved in some valved interatrial shunt devices after long-termimplantation, e.g., by 1 year. Further, shunts may develop bidirectionalshunting that was not present early on. Bidirectional shunting isindicative of an incompetent valve, e.g., a valve where one or moreleaflets do not fully coapt during closure, resulting in an open channelfor reversed flow, and depending on the severity of the incompetence,may create a potential path for paradoxical embolus to traverse from theRA to LA.

To assess the effective orifice size of valved shunts over time,transesophageal echo/Doppler measurements of the diameter of the venacontracta, measured on the left-to-right flow jets through the shunt,were found to be consistent with progressive shunt narrowing. The venacontracta diameter monotonically decreased with time after implantationfrom 4.0±1.1 mm just after implantation, to 3.6±1.0 mm at 3 months, and2.7±1.4 mm at 6-12 months (p<0.01). This equates, on average, to shuntslosing more than half of their orifice area by 12 months. Moreover, someof the left-to-right jets appeared to be exiting the shunt at an anglesubstantially different from the long axis of the shunt body. Thisskewing of the jet is consistent with material inside the shunt such asa valve leaflet with impaired mobility, which diverts the direction ofthe jet. This observation gives rise to concern about a decrease in theclinical effectiveness of the shunts over time

Clinical effectiveness also may be measured by the rate ofhospitalization for worsening heart failure. In the 38 patients, duringthe first 6 months after implantation of the V-Wave shunt, thehospitalization rate was 0.16 per patient year, which increased to 0.40per patient year between months 6-12. These data suggest there may be aloss of shunting benefit consistent with the time course associated withshunt narrowing or occlusion.

There are several possible mechanisms working alone or in combinationthat could explain these observations.

The least likely cause of shunt occlusion is collapse of the shunt dueto external forces applied by the septum. For example, it is possiblethat contraction of pannus tissue formed during the later stages ofhealing (remodeling) could result in extrinsic compression of the shunt.However, there is no evidence to support this scenario based on multipleobservations of frame geometry seen during pre-clinical studies andduring follow-up transesophageal echocardiography (“TEE”), CT, orfluoroscopic imaging in humans. In all cases, the observed shunt framehas not been observed to be extrinsically compressed or in any other waynarrowed, deformed, or fractured.

Another possible mechanism is in situ thrombosis of the shunt. However,all patients were treated with monitored anticoagulation for the firstthree months, or indefinitely if there were other indications forchronic anticoagulation, which was most commonly required in patientswith a history of atrial fibrillation. Subjects were also treatedsimultaneously with low-dose aspirin, which was continued indefinitely.Having experience with prosthetic cardiac valves as a predicate, valvethrombosis would have been expected to be seen earlier, typically within30-45 days after implantation, especially in patients with a history ofsubtherapeutic anticoagulation therapy.

In the 38 patients implanted with the V-Wave valved hourglass-shapedshunt described above, no thrombi were detected on 121 consecutivepost-implantation echocardiograms. These studies systematically lookedfor intracardiac or device thrombus by an independent EchocardiographicCore Laboratory at time points including one day after implantation, andat 1, 3, 6, and 12 months after implantation. None of the patientspresented with stroke or other clinical manifestations of thromboembolicevents. Of 9 patients with suspected shunt occlusion or incompetentvalves, most were taking therapeutic doses of anticoagulants (warfarinor New Oral Anticoagulant agents) at the time the shunt anomaly wasdiscovered. Another reason that thrombosis is unlikely is theobservation of progressive vena contracta narrowing over a time courseof 6 months or more. Thrombosis would be expected to result in suddenlumen loss, and not progress slowly over a period of months.

A third potential cause of occlusion is neoendocardial tissue overgrowthor pannus formation that narrows the lumen at the neck of thehourglass-shaped shunt. Applicants' earlier ovine studies suggestotherwise. Specifically, the shunt lumen surface at the neck of thehourglass contained only microscopic amounts of cellular material. Ongross pathological examination, there was no visible loss of the lumenarea in neck region. A human shunt specimen has been examined in anexplanted heart from a patient that underwent cardiac transplantation2.5 years after shunt implantation. The ePTFE surfaces of the shuntincluding the lumen at the neck contained no pannus formation ornarrowing of any kind.

In another example, a left atrial pressure sensor implanted across theFO by transseptal catheterization and used for guiding the medicaltherapeutic dosing in symptomatic patients with severe heart failure wasobserved to experience pannus formation. In the original embodiment ofthe sensor, the sensing diaphragm, located at the distal end of thesensor module body, protruded into the left atrium by 1-mm beyond itsthree anchoring legs that rested on the left atrial side of the septum.In a later, improved geometry version, the legs were placed moreproximal on the sensor module body so that sensing diaphragm protrudedinto the LA by an additional 1.5 mm.

In a comparative inter-species pathology study, neoendocardial tissue(pannus) formation was observed over the sensing diaphragm in 20 of 31original sensors compared with only 3 of 40 specimens with the improvedgeometry sensor. Of the 20 original sensors with tissue coverage, 7 haddemonstrable artifacts in the LA pressure waveform. In each case withartifacts, pannus formation over the sensing diaphragm had athickness >0.3 mm. These data indicate that when tissue coverage exceedsthis thickness, the tissue interferes with fluid pressure measurement.None of the improved sensors had waveform artifacts or tissuethickness >0.3 mm.

In addition to producing waveform artifacts, the time course of tissueencapsulation of the sensing diaphragm could be estimated by assessingLA pressure waveforms for baseline drift with or without the developmentof artifacts. It was hypothesized that as neoendocardial tissue growsover the sensing diaphragm, measured LA pressure increased due to adrifting baseline caused by tension applied from the tissue capsulecovering the diaphragm through its contiguous connection with the atrialwall. This healing phenomenon may be initiated as early as severalweeks' post implant in animals and starts around 3-4 months in humans.Using the timing of drift to indicate tissue coverage in humans, it wasshown that in a group of 46 heart failure patients with the originalsensor design geometry, about 25% developed the characteristic driftpattern associated with tissue coverage of the sensing diaphragm duringthe first year after implantation. Of 41 similar patients implanted withthe improved geometry sensor, none developed drift.

Pannus formation on devices that traverse the interatrial septum hasbeen observed to start at the portions of the device in contact with theseptum in the region of local tissue injury. Tissue growth progressescontiguously, extending translationally along the external surfaces ofthe device that protrude into each atrial chamber. This pannus growththins as a function of distance from the sites of cardiac contact untilit becomes essentially a monolayer of neoendothelial cells. The processnaturally stops after about 6-12 months in humans. Thereafter, theremaining tissue may remodel but active growth of pannus is completed.From these data, Applicants observed that tissue coverage typicallygrows a distance of about 3 mm from its starting place on the septalwall before stopping or becoming thin enough so as not to impede devicefunction.

Thus, for pannus to cause narrowing of the lumen at the shunt neck, itwould have to extend contiguously from the site of injury on the septumfor some distance to reach the neck. Applicants have determined thattranslational tissue growth over a distance of 3 or more millimetersbecomes much less likely.

Pannus formation affecting the valve leaflets is the most likelystand-alone mechanism that explains all of the untoward observationsseen in human subjects implanted with V-Wave shunts, includingprogressive shunt narrowing, incompetence of the valve withbidirectional flow, and eventual loss of shunt flow with associated lossof clinical efficacy.

Tissue overgrowth affecting the valve leaflet bases and commissures wasthe predominant histopathological finding in the ovine pre-clinicalstudy described above. Gross pathological examination of shuntsimplanted for 3 months showed pannus infiltration extending from theadjacent FO into the valve leaflet bases with thickening of the leafletbodies in 5 out of 6 shunts. In 4 shunts, there was fusion of at least 2of the 3 valve commissures where the leaflet edges were sutured to theshunt frame. Fusion of all 3 commissures was observed in 3 shunts. Onecase showed severe narrowing at the commissures with a luminal area of 4mm² or a 75% area stenosis in comparison to the normal 19.6 mm² lumen atthe device neck. The leaflets were described as semi-pliable orstiffened in 4 out of 6 shunts. In two of the devices, commissuralfusion and leaflet thickening were so pronounced that complete leafletcoaptation could not likely occur during valve closure. In none of thesecases has pannus formation been seen to narrow the shunt neck.

On examination of microscopic sections, pannus thickness tends to begreater on the side of the leaflets facing the atrial septum where theePTFE/leaflet junction was infiltrated with pannus that was contiguouswith the adjoining atrial tissue. Pannus extended from the atrial septumon and around the right atrial edge of the ePTFE skirt and into the baseand commissures of the valve leaflets. At 3 months, the pericardialleaflets showed varying degrees of pannus coverage ranging from mild tomarked. In general, pannus is thickest at the leaflet bases andcommissures, and tapers toward the free edges. In 2 sheep, the pannus onthe leaflets measured 2 to 3 times the original thickness of theleaflets.

The pannus was generally well healed or organized by 3 months. It wascomposed of collagen and proteoglycan matrix surrounding smooth musclecells, fibroblasts and rare focal areas of inflammation withlymphocytes, macrophages, and occasional multinucleated (foreign bodytype) giant cells. The pannus tissue was mostly covered withneoendothelium consistent with near complete healing. No leafletcalcification or thrombi were observed.

Although animal models of cardiovascular devices are limited in theirability to represent human tissue healing responses, the majordifferences are characteristically limited to the temporal duration ofthe response. For example, in a comparative pathology study described inthe publication, “Comparative Pathology of an Implantable Left AtrialPressure Sensor” by Roberts, et al., of a percutaneously implantabletitanium/nitinol-enclosed LA pressure sensor, implanted on theinteratrial septum, it was found that sheep at 1.5 to 8 months andcanines implanted for 1 to 25 months, closely approximated thepathological findings seen in humans implants of 3 to 56 monthsduration. Histology had a similar appearance in humans and animals, andconfirmed that the tissue covering the device was composed of aneoendocardium lined with a neoendothelium. The appearance of theneoendocardial tissue covering the sensor described above was similar towhat is observed with ASD closure devices.

This mechanism of pannus formation preferentially affecting thebioprosthetic valve material compared to the ePTFE encapsulated portionsof the shunt was observed in the human explanted specimen referred toearlier. After 2.5 year of implantation in heart, the 3 pericardialleaflets were severely thickened, immobile, infiltrated at their basesand commissures with pannus resulting in valvular stenosis with areduction in outflow area of 52% relative to the non-obstructed shuntneck. Although this shunt was patent, it would have been incompetent,allowing bidirectional flow, and would have shunted less than half ofthe flow expected for any given pressure gradient.

To further evaluate the tendency of this bioprosthetic valve to becomeinfiltrated with pannus, valved and valveless designs of the V-Waveshunt were implanted by applicants in a non-diseased juvenile ovine(n=9) model. Specifically, this study was designed to highlight theresistance of a valveless, ePTFE encapsulated shunt (n=6) to pannusformation, narrowing and occlusion, relative to the legacy valvedversion previously used in humans (n=3), by creating a highlyproliferative model expected in healthy juvenile sheep where theleft-to-right interatrial pressure gradient was expected to be small. Inthe valveless design, the bioprosthetic valve material and its attachingpolypropylene suture were removed and the ePTFE encapsulation wasextended to cover the entire nitinol frame of the shunt except for thelast 1.5 mm on the RA side where the shunt was coupled to its deliverysystem for deployment. The ePTFE used had an internodal distance of upto 30 microns. At 12 weeks the sheep where euthanized. The grosspathology findings showed that the 3 valved shunts were heavilyinfiltrated with pannus formation, extending from the septum into theregions containing the bioprosthetic leaflets. The leaflets were fused,immobile and highly stenotic leaving only a pinhole opening. The degreeof pannus formation was much exaggeration versus prior experience in theovine heart failure model. Thick pannus extended retrograde contiguouslyfrom the leaflet bases toward the hourglass neck of the shunts. Thepannus growth from the original septal site of injury to the tips of thevalve leaflets exceeded 3 mm in distance. Pannus appeared to growthrough the valve commissures and through the suture holes attaching theporcine pericardial leaflets to the frame and the ePTFE skirt. Pannusformation was associated with mononuclear inflammatory cell infiltratesand multinucleated giant cells.

All 6 of the valveless, ePTFE encapsulated shunts were widely patentwith only minimal pannus formation attaching the FO tissue to theexternal surface of the device. Applicants observed no pannus growingtranslationally more than 3 mm along the external surface of the ePTFEfrom the septum. No visible pannus reached from the septum all the wayinto the lumen portion of either the left atrial entry cone or rightatrial exit cone of the device. The lumina at the necks of all of theshunts were widely patent on gross and microscopic examination. Therewas no evidence of pannus formation permeating through the ePTFEencapsulation into the shunt lumen.

From these combined observations, applicants have determined that lengthof translational pannus growth from the site of healing may be dependenton the type of biomaterial surface. In the case of the ePTFEencapsulated shunt, pannus formation severe enough to interfere withdevice function tends to translate a maximum of about 3 mm from the siteof injury, whereas in the case of the bioprosthetic valve materialtested, the amount of pannus formation and translational length ofpannus tissue growth were exaggerated.

Also, from these data, it is reasonable to expect that the near completeshunt healing seen after 3 months in the juvenile ovine model will bepredictive of the histopathological findings in humans at 9-12 months.Moreover, these gross and microscopic observations, with theiranticipated species-to-species conservation of findings, leads to theconclusion that the healing response in sheep is likely indicative ofthe mechanism causing shunt closure, valvular incompetence, andprogressive stenosis in humans. Thus, there exists a need for a moredurable shunt configuration that maintains luminal patency for extendedperiods of time.

It further would be desirable to provide a shunt for redistributingatrial blood volumes and reducing interatrial pressure imbalances thatreduces the risk of paradoxical embolism caused by emboli transfer fromthe right to left atria.

It also would be desirable to provide an interatrial shunt configurationthat reduces the risk of pannus formation after a prolonged period ofimplantation, where the degree of pannus formation and tissue ingrowthis not strongly dependent on the manner or location in which the shuntis implanted in the FO.

SUMMARY OF THE INVENTION

In view of the foregoing drawbacks of previously-known interatrialshunts, an asymmetric shunt constructed in accordance with theprinciples of the present invention provides a more durableconfiguration that maintains luminal patency for extended periods oftime. The inventive asymmetric shunts further enable redistribution ofinteratrial blood volumes and pressure imbalances while reducing a riskof paradoxical embolism caused by emboli moving through the shunt fromthe right to left atria.

The asymmetric device for regulating blood volume distribution across apatient's atrial septum includes a first expandable end regiontransitionable from a contracted delivery state to an expanded deployedstate in which the first expandable end region extends into thepatient's left atrium and an inlet end of the first expandable endregion is in a first plane, and a second expandable end regiontransitionable from a contracted delivery state to an expanded deployedstate in which the second expandable end region extends into thepatient's right atrium and an outlet end of the second expandable endregion is in a second plane. The first plane intersects the secondplane, e.g., at an angle between 20 and 45 degrees. In addition, theasymmetric device includes a neck region joining the first expandableend region to the second expandable end region, the neck region sizedand shaped for placement in the patient's atrial septum. The asymmetricdevice may be formed of a plurality of longitudinal strutsinterconnected by a plurality of circumferential sinusoidal struts.

In accordance with one aspect of the present invention, the inlet end ofthe first expandable end region has a first cross-sectional shape, e.g.,a circle, and the outlet end of the second expandable end region has asecond cross-sectional shape different from the first cross-sectionalshape of the inlet end of the first expandable end region, e.g., across-sectional shape having a first pair of opposing sides that extendparallel and a second pair of opposing ends that curve, in the expandedstate. In addition, the asymmetric device has a central longitudinalaxis. From a first profile of the device having a first orientation, thecentral longitudinal axis has a curved shape. In accordance with anotheraspect of the present invention, the central longitudinal axis of thedevice lies in a single plane.

In addition, the asymmetric device may include a conduit having a lumenwall defining a lumen, wherein the lumen wall is resistant to transmuraland translational tissue growth. For example, the lumen may have adiameter in the neck region in a range of 5 mm to 6.5 mm, and mayprovide high velocity flow therethrough, while limiting paradoxicalemboli passing across the lumen during a transient pressure gradientreversal. The conduit may include a layer of biocompatible material. Theconduit may have a first end that extends from the neck region a firstdistance of at least 3 mm into the patient's left atrium and a secondend that extends from the neck region a second distance of at least 3 mminto the patient's right atrium, thereby preventing pannus formationfrom narrowing the lumen of the conduit in the neck region. The secondend of the conduit may extend from the neck region a distance of between3 mm to 15 mm into the patient's right atrium.

Further, the conduit may be sized and shaped so that when implanted thesecond end of the conduit is located out of a natural circulation flowpath of blood entering into the patient's right atrium from an inferiorvena cava, thereby reducing a risk of emboli entrained in flow from theinferior vena cava being directed into the second end of the conduit. Inaddition, the first expandable end region of the asymmetric device, inthe expanded deployed state, may form a filter that prevents emboli fromentering the second end of the conduit.

In accordance with another aspect of the present invention, theasymmetric device for regulating blood volume distribution across apatient's atrial septum includes a first expandable end regiontransitionable from a contracted delivery state to an expanded deployedstate in which the first expandable end region extends into thepatient's left atrium and an inlet end of the first expandable endregion has a circular cross-sectional shape in the expanded state, and asecond expandable end region transitionable from a contracted deliverystate to an expanded deployed state in which the second expandable endregion extends into the patient's right atrium and an outlet end of thesecond expandable end region has a cross-sectional shape in the expandedstate having a first pair of opposing sides that extend parallel and asecond pair of opposing ends that curve. The asymmetric device may havea central longitudinal axis, wherein from a first profile of the devicehaving a first orientation, the central longitudinal axis is a straightline; whereas, from a second profile of the device having a secondorientation, the central longitudinal axis has a curved shape. Forexample, at the second orientation of the second profile of the device,one of the first pair of opposing sides that extend parallel of thecross-sectional shape of the second expandable end region in theexpanded state is closest to the first expandable end region.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A to 1C are, respectively, perspective, end and side views of aninteratrial shunt.

FIG. 2 is a side view of an alternative embodiment of an interatrialshunt having a cutout in its polymeric encapsulation to secure the shuntto a delivery system.

FIGS. 3A and 3B are, respectively, a plan view of the right atrial sideof the atrial septum, illustrating implantation of a shunt through aportion of the fossa ovalis, and a perspective view of an embodiment ofthe shunt of FIGS. 1A-1C positioned in the fossa ovalis of the atrialseptum.

FIGS. 4A and 4B schematically depict pannus formation on anhourglass-shaped embodiment of an interatrial shunt positioned in thefossa ovalis orthogonal to the atrial septum wall, immediately afterimplantation and after pannus formation.

FIGS. 5A and 5B schematically depict pannus formation on anhourglass-shaped embodiment of an interatrial shunt positioned in thefossa ovalis non-orthogonal to the atrial septum wall, inventionimmediately after implantation and after pannus formation.

FIGS. 6A to 6D illustrate various perspectives of an alternativeexemplary embodiment of a shunt constructed in accordance with theprinciples of the present invention.

FIG. 6E illustrates the shunt of FIGS. 6A to 6D with respect to theatrial septum in an expanded deployed configuration.

FIGS. 7A to 7E illustrate various perspectives of another alternativeexemplary embodiment of a shunt constructed in accordance with theprinciples of the present invention.

FIG. 7F illustrates the shunt of FIGS. 7A to 7E with respect to theatrial septum in an expanded deployed configuration.

FIGS. 8A to 8D illustrate various perspectives of yet anotheralternative exemplary embodiment of a shunt constructed in accordancewith the principles of the present invention.

FIG. 8E illustrates the shunt of FIGS. 8A to 8D with respect to theatrial septum in an expanded deployed configuration.

FIGS. 9A to 9D illustrate various perspectives of an alternativeexemplary embodiment of a shunt constructed in accordance with theprinciples of the present invention. FIG. 9E illustrates the shunt ofFIGS. 9A to 9D with respect to the atrial septum in an expanded deployedconfiguration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Interatrial shunts are provided for redistributing interatrial bloodvolumes and reducing left atrial pressure, which may be advantageous intreating subjects suffering from heart failure (“HF”) or other disordersassociated with elevated left atrial pressure. A preferred embodiment ofthe inventive device includes an anchor, which may be an hourglass or“diabolo” shaped stent or frame, and a conduit, formed by encapsulatingthe frame in a synthetic biocompatible material. The shunt is configuredto be lodged securely within a passage formed in the atrial septum,preferably the fossa ovalis, and provides one-way blood flow from theleft atrium to the right atrium, when blood pressure in the left atriumexceeds that on the right.

Referring now to FIGS. 1A to 1C, an illustrative embodiment of aninteratrial shunt is described. Shunt 10 may be constructed similar tothe shunt designs disclosed in U.S. Pat. No. 10,076,403, assigned to theassignee of the instant application, the entire contents of which areincorporated by reference herein. For example, shunt 10 includes anchor12 having three regions: flared or funnel-shaped end region 14, flaredor funnel-shaped end region 18, and neck region 16 disposed between endregions 14 and 18. Neck region 16 is configured to lodge in a punctureformed in the atrial septum, preferably in the fossa ovalis. Flared endregions 14 and 18 are configured to partially engage and protrude beyondthe right and left sides, respectively, of the atrial septum whenimplanted. Shunt 10 further comprises a conduit, illustratively formedby encapsulating anchor 12 with biocompatible material 20 that coversall or substantially all of anchor 12 to form a conduit defining a lumenor interior passageway 22.

Flared region 14 is configured to be disposed in the right atrium, whileflared region 18 is configured to be disposed in the left atrium. In oneembodiment, anchor 12 includes six longitudinal struts 24 interconnectedby five circumferential struts 26 a-26 e. As depicted in the figures, aconduit is formed by biocompatible material 20 that encapsulates theentirety of neck 16, flared end region 18, and flared end region 14.Biocompatible material 20 preferably is affixed to anchor 12 using asuitable biocompatible adhesive or by sandwiching the anchor betweeninner and outer layers of biocompatible material using sinteringtechniques.

The radial dimensions, axial lengths and contours of neck region 16 andflared end regions 14 and 18 preferably are selected to provide laminarflow through the interior of the shunt, to reduce the formation of eddycurrents when implanted, and thus inhibit thrombus formation; to inhibitpannus formation that could obstruct the neck region; to promote tissueingrowth around the exterior of the neck region to secure the shuntagainst migration; to provide a desired rate of blood flow between theleft and right atria at physiological pressure differentials; and toprevent retrograde paradoxical embolization.

As noted above, neck 16 of shunt 10 preferably is configured forimplantation through the fossa ovalis of the atrial septum, and morepreferably near or at the central portion of the fossa ovalis. As knownto those skilled in the art, the fossa ovalis is a thinned portion ofthe atrial septum formed during fetal development of the heart, whichappears as an indent in the right side of the atrial septum and issurrounded by a thicker portion of the atrial septum. While the atrialseptum itself may be several millimeters thick and muscular, the fossaovalis may be only approximately one millimeter thick, and is formedprimarily of fibrous tissue.

Shunt 10 may be asymmetrically shaped to take advantage of the naturalfeatures of the atrial septum near the fossa ovalis, and to providesuitable flow characteristics. For example, the anchor may have anhourglass or diabolo shape where a LA entry funnel resembles aconical-shaped nozzle and a RA exit funnel is “bell” shaped, with thewide mouth lumen of the bell at the RA exit port in the RA. The narrowentrance to the bell-shaped exit funnel connected to the orifice of theneck region may be configured to approximate the curved surface of aparabola. This type of convergent-divergent nozzle resembles the shapeof a classical de Laval nozzle used in rocket engines. Left to rightflow is largely governed by the smooth convergence of streamlines in theentry cone and the divergence of streamlines exiting the bell. Such anozzle configuration is very efficient in the forward flow directionhaving a discharge coefficient resembling a classic venturi tube, e.g.,0.95-0.98.

Referring now to FIG. 1C, points B and C are located on the leftmostcircumferential strut 26 e, which defines the LA entry port. Points Aand D are located on circumferential strut 26 d along the LA entryfunnel proximal to strut 26 e. Points H and E are located oncircumferential strut 26 b along the RA exit funnel, and points G and Fare located on circumferential strut 26 a, which defines the RA exitport. In preferred embodiments, the diameter of lumen 22 in the neckregion of the shunt orifice ranges from 5 to 6.5 mm. The portion of theshunt crossing the FO, bounded by points ADEH may be 3 mm in axiallength but may be extended up to 10 mm in patients with a thicker FO.The diagonal length between points AB, CD, EF, and/or GH is preferably≥3 mm so that pannus cannot grow translationally inward from the ends ofthe shunt and thus obstruct neck region 16. In addition, the horizontalcomponent length between points AB, CD, EF, and/or GH is preferably ≤15mm, to avoid interference with existing cardiac structures whenimplanted. It has been determined that providing a length of segments EFand GH generally greater than 5 mm is expected to ensure that the endregion that extends into the right atrium is disposed generally out ofthe flow path of blood returning from the inferior vena cava, which ismost likely to have entrained emboli that could cause paradoxicalembolization. Truncated funnel cones bounded by ABCD and/or EFGH mayhave volumes 2 ml.

Other embodiments of the shunt may include anchors with differentcombinations and configurations of circumferential ring and axial strutelements. Specifically, such embodiments, may have more or less than 6longitudinal struts 24 and more or less than five circumferential struts26 a-26 e. These configurations may yield other shunt lumen geometries.In another embodiment, anchor 12 may be made of a self-expandingpolymer. Alternatively, the anchor need not be self-expanding, and maybe made from a plastically deformable biocompatible metal such as 316 Lstainless steel, cobalt chromium alloys, or any other such suitablematerials known to those skilled in the art. Such a deformable shuntanchor may be delivered by an expanding member, such as a balloon, thatis configured to achieve the desired luminal geometry. The deformableanchor may be designed to expand prismatically or at certain localizedsites where ductile hinges are configured for more selected expansion astaught by U.S. Pat. No. 6,242,762 to Shanley, the entire contents ofwhich are incorporated by reference herein.

Referring now to FIG. 2, an alternative embodiment of an interatrialshunt is described. Shunt 30 includes anchor 31 is similar inconstruction to that described for the embodiment of FIGS. 1A-1C, andhas flared end regions 32 and 33 and neck region 34. When implanted in apatient's interatrial septum, flared end region 32 is disposed in thepatient's right atrium, while flared end region 33 is disposed in thepatient's left atrium, with neck region 34 situated in a passage formedin the interatrial septum. Anchor 31 includes longitudinal struts 35 andcircumferential struts 36 a-36 e, and is encapsulated by biocompatiblematerial 37. Anchor 31 may comprise a self-expanding or plasticallydeformable material as described herein above.

Shunt 30 of FIG. 2 differs from the previous embodiment in thatbiocompatible material 37, for example ePTFE, includes cutout 38adjacent to circumferential strut 36 a. Cutout 38 may extend proximallyfrom circumferential strut 36 a for a distance of 0.5 mm to 2 mm, andmore preferably about 1 mm, to permit circumferential strut 36 e to bereleasably engaged with a delivery system during deployment, forexample, hooks, as described in U.S. Pat. No. 9,713,696 to Yacoby, theentire contents of which are incorporated by reference herein.Biocompatible material 37 may be trimmed manually or mechanically fromcircumferential strut 36 a to create cutout 38 or by laser-cutting. Inthis manner, shunt 30 may be positioned and repositioned in a passageformed in the interatrial septum until the clinician is satisfied withthe device placement, before being released. In a preferred embodiment,the conduit formed by biocompatible material 37 extends a distance of atleast 3 mm beyond neck region 34 into flared end region 32, to ensurethat pannus cannot grow translationally along luminal wall far enough topartially occlude the flow area of neck region 34. Additionally, flaredend region 32 extends a distance of at least 5 mm into the right atriumwhen implanted in the interatrial septum to ensure that the entry offlared end region 34 is generally not aligned with flow paths generatedby blood entering the right atrium from the inferior vena cava, therebyreducing the risk that emboli carried from the lower extremities intothe right atrium will cause paradoxical embolism by passing throughshunt 30.

The interatrial hourglass-shaped shunt with flow characteristicsresembling a venturi tube and a discharge coefficient of approximately0.96-0.97 may have a minimal neck orifice inner diameter ranging from 5mm to approximately 6.5 mm. Having a somewhat larger orifice diameter,within this range, e.g. 6.0 mm, will support approximately 35% more flowfor any given pressure gradient compared with a 5.1 mm shunt. This maynot only create improved hemodynamic conditions but provide additionalbenefit in maintaining shunt flow should some shunt narrowing due topannus ingrowth occur during device healing.

In addition, various nozzle geometries with high discharge coefficientsrelative to an orifice-plate geometry advantageously may be used toprovide laminar flow through the shunt. These include but are notlimited to various variations of venturi tubes, conical convergentnozzles (with convergence angles from 20 to 80 degrees), cylindricalconvergent nozzles, and the Addy type nozzle with a convergent curvedentrance wall leading to a length of cylindrical tubing having adiameter equivalent to the orifice diameter. The latter two appearsimilar in appearance to the horn of a trumpet. In another preferredembodiment, the shunt lumen may be a cylindrical tube with no or minimaldilation at the entry or exit ports.

The cross-section of lumen 22 (see FIG. 1B) need not be circular and/orthe lumen need not be coaxial with a straight horizontal line axis whenviewed longitudinally. Although these latter geometries may be difficultto deliver through catheters with circular luminal cross-sections, theymay be constrained to such catheter lumens and expand into non-circularcross-sectional or curved longitudinal geometries upon deployment. Otherpreferred embodiments include any combination of entry, orifice, andexit geometries where the exiting jet vena contracta cross-sectionalarea is 70% or greater compared with the minimal orifice area, over therange of physiological interatrial pressure gradients, thereby having ahigher discharge coefficient than an orifice-plate.

A shunt with a single LA conical entry funnel, with an hourglass-shapedlumen, or with a tubular lumen, having a discharge coefficient of 0.70or larger, generally has a longer tunnel of entrained flow by nature ofits longer length, typically 6 to 30 mm long, versus an orifice-platemesh type shunt, which may be defined by the thickness of the FO itselfand is typically shorter than 6 mm, e.g., 3 mm or less. For paradoxicalembolization to occur, i.e., for a paradoxical embolus to embolize fromthe heart into the systemic arterial circulation, the paradoxicalembolus must pass completely or nearly completely through the shunt.Emboli may be propagated by their residual kinetic energy against aleft-to right gradient or when there is no gradient, or may be carriedalong when a reversed pressure gradient creates right to left bulk flow.Depending on the relative magnitude of the kinetic energy of the embolusand the bulk flow directional status, a longer lumen shunt will tend topass fewer emboli compared to an orifice-plate shunt with a shorterlumen. This is likely to be the case in the presence of normal left toright bulk flow or when there is zero net flow. This is also likely tobe true during very transient pressure gradient reversals, such asduring a cough. Therefore, in another preferred embodiment, a shunt witha flow lumen length of 6 to 30 mm, or more typically 10 to 15 mm, byvirtue of its increased lumen length, will have less tendency forparadoxical embolization than an orifice-plate mesh shunt.

Referring now to FIG. 3A, a preferred location for implanting shunt 10of FIGS. 1A-1C is described. FIG. 3A is a plan view of the right atrialside of atrial septum 40, including implantation site 41 located at acentral position of fossa ovalis 42. Preferably, implantation site 41 isselected so that the shunt may be implanted spaced apart from thesurrounding limbus 43, inferior vena cava (“IVC”) 44, and atrial septum45. For example, as shown in FIG. 3B, flared end region 14 is configuredto be implanted in right atrium 46 and may be tapered so as to have amore cylindrical shape than does flared end region 18, which isconfigured to be implanted in left atrium 47. The more cylindrical shapeof flared end region 14 may reduce or inhibit contact between flared endregion 14 and limbus 43 of fossa ovalis 42, that is, between flared endregion 14 and the prominent margin of the fossa ovalis, while stillanchoring device 10 across atrial septum 45. The more cylindrical shapeof flared end region 14 further may reduce or inhibit contact betweenflared end region 14, and the right side of atrial septum 40, as well asridge 49 separating the coronary sinus from the IVC 44 (shown in FIG. 3Abut not FIG. 3B).

Still with respect to FIG. 3A, a preferred location for shuntimplantation may be slightly anterior to the centerline of the long axisof the fossa ovalis, i.e., located on the right hand side of the ovale.This location leaves potential space in the upper left quadrant(posterior-superior) of the fossa, which has been found to be optimalfor crossing the fossa to perform structural heart disease procedures onthe mitral valve, including edge-to-edge repair with MitraClip®transcatheter mitral valve repair system offered by Abbott, Abbott Park,Ill. and mitral annuloplasty with Cardioband, offered by Valtech Cardio,Or Yehuda, Israel. This preferred location also leaves potential spacein the lower left quadrant (posterior-inferior) of the fossa, which hasbeen found to be optimal for crossing the fossa to perform structuralheart disease procedures to occlude the left atrial appendage. A shuntwith an hourglass shape that occupies the smallest possible location onthe fossa, as described herein, facilitates these other procedures.

Again, referring to FIG. 3B, shunt 10 preferably is configured so as toavoid imposing significant mechanical forces on atrial septum 45, thusallowing the septum to naturally deform as the heart beats. For example,the thicknesses of muscular areas of septum 45 may change by over 20%between systole and diastole. It is believed that any significantmechanical constraints on the motion of atrial septum 45 in such areaswould lead to the development of relatively large forces acting on theseptum and/or on atrial tissue that contacts shunt 10. Such forces couldinvoke an inflammatory response and/or hyperplasia in the atrial septumtissue, and possibly cause shunt 10 to eventually lose patency. However,by configuring shunt 10 so that neck region 16 may be implanted entirelyor predominantly in the fibrous tissue of the fossa ovalis 42 with asmall footprint, the hourglass shape of shunt 10 is expected to besufficiently stable so as to be retained in the septum, while reducingmechanical loads on the surrounding atrial septum 45. Tissue ingrowthfrom atrial septum 45 in regions 48 may further enhance binding of shunt10 to the septum. Preferably, there should be a substantial rim of fossaaround the shunt after implantation, e.g., for a thickness of 1-2 mm, asdepicted in FIG. 3B.

Also, because neck region 16 of shunt 10 is significantly narrower thanflared end regions 14 and 18, shunt 10 will “self-locate” in a puncturethrough atrial septum 45, particularly when implanted through the fossaovalis, with a tendency to assume an orientation where its longitudinalaxis is substantially orthogonal to the FO. In some embodiments, neckregion 16 may have a diameter suitable for implantation in the fossaovalis, e.g., that is smaller than the fossa ovalis, and that also isselected to inhibit blood flow rates exceeding a predeterminedthreshold. Neck region 16 preferably provides a passage having adiameter between about 4 and about 7 mm, and more preferably betweenabout 5 mm and about 6.5 mm. For example, diameters of less than about 4mm may in some circumstances not allow sufficient blood flow through theshunt to decompress the left atrium, and may reduce long-term patency ofthe shunt. Conversely, diameters of greater than about 7 mm may allowtoo much blood flow, resulting in right ventricular volume overload andpulmonary hypertension. Preferably, the effective diameter at thenarrowest point in shunt 10 is about 5 mm to 6.5 mm.

The diameters of flared end regions 14 and 18 further may be selected tostabilize shunt 10 in the puncture through atrial septum 45, e.g., inthe puncture through fossa ovalis 42. For example, flared end region 18may have a diameter of 10 to 20 mm at its widest point, e.g., about 13to 15 mm; and flared end region 14 may have a diameter of 9 to 15 mm atits widest point, e.g., about 9 to 13 mm. The largest diameter of flaredend region 14 may be selected so as to avoid mechanically loading thelimbus of the fossa ovalis 42, which might otherwise cause inflammation.The largest diameter of flared end region 18 may be selected so as toprovide a sufficient angle between flared end regions 14 and 18 tostabilize shunt 10 in the atrial septum, while limiting the extent towhich flared end region 18 protrudes into the left atrium (e.g.,inhibiting interference with flow from the pulmonary veins), andproviding sufficient blood flow from the left atrium through neck region16.

The length of end region 14 may be selected to protrude into the rightatrium by a distance sufficient to inhibit tissue ingrowth that mayotherwise interfere with the operation of shunt 10. Applicants haveobserved that tissue ingrowth inwards along an impermeably membranes ofspecified biomaterials from the end that contacts tissue generally stopsafter about 3 mm. Accordingly, to ensure that tissue ingrowth from theends of the conduit does not extend into and partially occlude the flowarea of neck region 16, the distance R between the narrowest portion ofneck region 16 and the end of region 14 should be at least 3 mm plushalf of the thickness of the septal region, i.e., fossa ovalis,contacting the exterior of shunt 10. Assuming that the fossa ovalis hasa thickness of about 3.0 mm, then the minimum distance R should be about4.5 mm, based on applicants' observations. Likewise, end region 18preferably does not significantly engage the left side of atrial septum45, so that distance L also preferably is at least 4.5 mm. Due topatient-to-patient variability in the thickness of the FO, e.g., due tothe patient's general health and age, and because neck region 16 may notbe precisely aligned with the mid-point of the FO, each distances R andL preferably fall within a range of 3 to 6 mm. Accordingly, for someembodiments, the overall dimensions of shunt 10 may be about 9-12 mmlong (L+R, in FIG. 3B) to prevent tissue ingrowth from the ends of theconduit, i.e., end regions 14 and 18, from partially occluding neckregion 16.

In another preferred embodiment, regardless of the geometrical shape ofthe conduit, there should be a minimum of 3 mm of material resistant totranslational tissue growth, i.e., extending inward from the ends of theend regions to accommodate neoendocardial tissue growth over the shuntsurfaces starting from a location in contact with the atrial septum,such that tissue growth cannot reach the orifice (site of minimaldiameter of the shunt lumen or cross-sectional area of lumen 22 shown inFIG. 1B). With this preferred embodiment, the minimal orifice diameterof an interatrial shunt device will be rendered largely unaffected bypannus formation. In another preferred embodiment, there should be aminimum of 3 mm of conduit length for neoendocardial tissue to grow overthe shunt luminal surfaces starting from a location in contact with theatrial septum, before reaching the entrance or exit port sites of theshunt lumen. With such an embodiment, there is even less potential forpannus to encroach the shunt lumen.

Referring now to FIGS. 4A and 4B, the expected healing response invokedby implanting shunt 10 of FIGS. 1A-1C orthogonally across the FO isdescribed, while FIGS. 5A and 5B correspond to implantation of the shuntnon-orthogonally so that an outer surface of the LA entry cone contactsthe atrial septal tissue. FIGS. 4A and 5A depict positioning of theshunts immediately post implantation, while FIGS. 4B and 5B depict shuntpositioning after the completion of the healing phase.

In each of FIGS. 4A and 4B, the FO is shown as bowed towards the RA andconcave towards the LA. In patients with dilated cardiomyopathy orrestrictive physiology, including most patients with left ventricularfailure, regardless of etiology, the FO portion of the interatrialseptum generally is bowed toward the right atrium. This gives the LA agenerally concave or near hemispherical shape in the region centered onthe FO. Conversely, the RA side of the FO is generally convex in shape.This orientation of the FO was confirmed by echocardiography (n=178examinations) in the 38 patients implanted with the V-Wave Nitzan-typevalved shunt discussed in the Background of the Invention portion ofthis specification. In measurements of more than 100 patients exhibitingheart failure with preserved ejection fraction (“HFpEF”), the LA volumegenerally averaged 85 ml with a minimum volume of 54 ml, while for alike number of patients exhibiting heart failure with reduced ejectionfraction (“HFrEF”), the LA volume generally averaged 104 ml with aminimum volume of 71 ml. Although the LA is often approximated by asphere or an ellipsoid, there are frequently exceptions to this, forexample, where the LA appears squashed when viewed in itsanterior-posterior dimension. Although not specifically quantified, theRA appeared to be similar in size to the LA.

Although exceptions to RA bowing of septal anatomy occur, they generallydo so in the presence of isolated right ventricular failure or severepulmonary hypertension in the absence of left ventricular dysfunction ormitral valve disease, e.g. as occurs in pulmonary arterial hypertension(“PAH”). In those instances, RA pressure tends to exceed LA pressurecausing the FO to bow in the opposite direction toward the LA. Suchpatients generally would derive no clinical benefit from left-to-rightinteratrial shunting. However, patients with severe pulmonaryhypertension in the absence of left-sided heart failure may benefit fromright-to-left shunting as a means to improve low systemic cardiacoutput. Several of the embodiments described in this disclosure would beprovide improved performance compared to right-to-left shunts currentlyavailable to that population of patients.

Another geometrical constraint is the frequent presence or need to placetransvenous endocardial electrical pacing or defibrillation leads in orthrough the RA of heart failure patients. In the 38-patient feasibilitystudy conducted with the V-Wave Nitzan-type shunt, 74% of patients hadalready been implanted with cardiac rhythm management devices prior tointeratrial shunting. Most of these patients had 2 or 3 such electricalleads placed. Leads most often enter the RA from the superior vena cava(“SVC”). Right atrial pacing leads usually loop up and terminateanterio-laterally in the RA appendage, but in some circumstances, theyare attached to a muscular portion of the interatrial septum. RV pacingand defibrillation leads usually course along the lateral wall of theRA, then cross the tricuspid valve, and terminate in theinterventricular septum, RV apex, or pulmonary outflow tract. LV leadsenter the coronary sinus, which is just below and anterior to the FO.Occasionally, leads must be placed from unusual sites of origin and mayenter the RA from the inferior vena cava (“IVC”). Leads are usually leftwith enough slack so that they do not put tension on their terminal endswhen the heart moves or changes position. Much of this slack results ina web of excess lead body material that is often concentrated in the RA.

The observations of septal bowing, the range of chamber dimensionsobserved and the consequences of multiple transvenous endocardial leadplacement have important implications for interatrial shunt devicedesign. If a shunt protrudes into the LA chamber, it preferably isplaced so that it generally projects orthogonally with respect to the FOas shown in FIG. A. Orthogonal placement is expected to minimizeimpingement on other adjacent or nearby critical cardiac structures,such as the aortic root, the mitral valve annulus, the roof and theposterior wall of the LA, and the pulmonary veins. Alternatively, if notplaced substantially orthogonally, as shown in FIG. 5A, the shuntgeometry should be selected to prevent the shunt from interacting withthese structures. Proper accounting for such design considerations willprevent erosion of the shunt into critical cardiac structures, andprevent blockage of flow through the shunt by luminal impingement byadjacent cardiac structures. Ideally, the shunt should also occupyminimal space within the LA and only minimally disturb its normal flowpattern. The LA fills from the pulmonary veins during ventricularsystole and drains into the left ventricle when the mitral valve opensduring diastole. Blood coming from the right superior pulmonary veinstends to course along and hug the interatrial septum preventing stasisnear the FO.

In a preferred embodiment of shunt 10, the volume of blood displaced bythe portion of the shunt protruding into the LA, i.e., the volume ofblood in the portion of the shunt lumen protruding into the LA, shouldbe less than or equal to 5% of the LA diastolic volume expected in thepatient population. This is typically 2.0 ml or less in adult patientswith heart failure. Moreover, the shunt should not protrude into the LAby more than 15 mm, or more typically 3 to 10 mm. These dimensionalconsiderations may also be accomplished in conjunction with other shuntfeatures that facilitate a substantially orthogonal orientation, such asan LA entry funnel.

Similar considerations exist for the RA side of the FO. The shunt shouldoccupy a minimal volume and have only a small effect on normal flowpatterns. In a preferred embodiment, the same occupying volume andprotrusion distance considerations, apply to the RA side of the shunt,that is, the device and its lumen should occupy less than or equal to 5%of the RA diastolic volume, e.g., 2.0 ml or less in adult patients withheart failure, and protrude into the RA by no more than, for example, 15mm, or more typically 3 to 10 mm. These dimensional considerations canalso be accomplished in conjunction with other shunt features thatfacilitate a substantially orthogonal orientation, such as RA exitfunnel. These same criteria apply when the shunt is used in anapplication where RA to LA shunting is desirable, e.g., pulmonaryarterial hypertension (“PAH”). The shunt should protrude in the RA theleast amount necessary so that it does not foul pacing leads or abradetheir electrical insulation.

As described earlier, the propensity for venous thromboembolism (“VTE”)to cross in the retrograde direction through a shunt is expected to be afunction of not only the amount and duration of retrograde shunt flowfrom the RA to the LA, but also a result of the flow patterns in the RA.The path of flow in the adult RA is complex because blood enters thechamber from multiple sources which include the inferior vena cava(“IVC”), the superior vena cava (“SVC”), the coronary sinus and from theLA through the shunt. These flow paths include directional changes andasymmetries whose topology has been assessed by color flow Dopplerimaging and more recently from magnetic resonance velocity mapping.

Since the overwhelming majority of VTE in adult patients originate fromthe lower extremities and pelvic veins, the path traveled by paradoxicalemboli are most likely similar to the flow vectors for blood coming fromthe IVC. Flow from the inferior vena cava courses along the posteriorwall of the RA chamber before looping around the roof, where it isdirected toward the tricuspid valve by coursing along the interatrialseptum. The rest of the cavity generally contains pooled blood. Thus,blood entering the RA from the IVC forms a clockwise vortex descendingalong the RA side of the interatrial septum in most patients with normalanatomy. Advantageously, this flow pattern of blood downwards from theroof of the RA and along the interatrial septum reduces the risk ofblood pooling in the vicinity of neck region 16 of the inventive shunt10, thus reducing the risk of local thrombus formation due to bloodstasis. Further, these flow pathway observations suggest that a thrombusoriginating from inferior vena cava will a have a trajectory that passesvery close to the RA orifice of a naturally occurring secundum typeatrial septal defect or an orifice-plate mesh type shunt. Because inthis case thrombus is essentially presented by the flow path within theRA to the orifice, even a small reversal of shunt flow could embolizethe thrombus across the orifice into the LA.

Preferably, the shunt includes an exit port (end region 14) that extendsa distance into the RA, e.g., 3 to 15 mm, or more typically 5 to 10 mm,sufficient to place the orifice of the exit port out of the naturallyoccurring flow paths in the RA. In particular, the exit port projectspartially or completely through the stream of blood originating from theIVC that loops down across the interatrial septum. Such a shunt geometrythus will be expected to have a lower risk of paradoxical embolizationcompared with an orifice-plate mesh type shunt where the exit port isdirected at the passing looped IVC flow stream.

Referring now to FIGS. 6A through 6E, an exemplary embodiment of a shuntconstructed in accordance with the principles of the present inventionis provided. Shunt 50 is constructed similar to shunt 10 of FIGS. 1A to1C. For example, shunt 50 is formed of a metal frame and encapsulatedwith a biocompatible material. Specifically, shunt 50 generallycomprises an anchor having three regions: flared or funnel-shaped endregion 51 having inlet end 52, flared or funnel-shaped end region 54having outlet end 55, and neck region 53 disposed between end regions 51and 54. Neck region 53 is configured to lodge in a puncture formed inthe atrial septum, preferably in the fossa ovalis. Flared end regions 51and 54 are configured to partially engage and protrude beyond the rightand left sides, respectively, of the atrial septum when implanted. Shunt50 further comprises a conduit, illustratively formed by encapsulatingthe anchor with biocompatible material 56 that covers all orsubstantially all of the anchor to form a conduit defining a lumen orinterior passageway.

Flared region 51 is configured to be disposed in the right atrium, whileflared region 54 is configured to be disposed in the left atrium. In oneembodiment, the anchor includes six longitudinal struts 57interconnected by five circumferential struts 58 a-58 e. Longitudinalstruts 57 prevent foreshortening of the anchor during expansion, whilethe sinusoidal or serpentine bends in circumferential struts 58 a-58 epermit the anchor to transition between a radially collapsedsubstantially cylindrical delivery state to an expanded, flared,deployed state. As depicted in the figures, a conduit is formed bybiocompatible material 56 that encapsulates the entirety of neck region53, flared end region 54, and flared end region 51. Biocompatiblematerial 56 preferably is affixed to the anchor using a suitablebiocompatible adhesive or by sandwiching the anchor between inner andouter layers of biocompatible material using sintering techniques.

In a preferred embodiment, the anchor comprises a self-expandingmaterial, such as a shape memory alloy, and circumferential struts 58a-58 e are treated to expand a predetermined amount when deployed, sothat together with encapsulation 56, the passageway has a contour thatpermits substantially laminar flow between flared end section 51 (in theleft atrium) and flared end section 54 (in the right atrium). Thesinusoidal or serpentine bends in circumferential struts on flared endregion 52 preferably are 180 degrees out of phase with the sinusoidal orserpentine bends in neck region 53 and flared end region 54, so that thesinusoidal or serpentine bends do not extend beyond the ends oflongitudinal struts 57 in either the collapsed delivery state ordeployed state.

The anchor may comprise a biocompatible metal framework or laser-cutsolid metallic tube made from nitinol, titanium alloy, cobalt chromiumalloy, MP35n, 316 stainless steel, L605, Phynox/Elgiloy, platinumchromium or other biocompatible metal such as are known to persons ofskill in the art. While a preferred embodiment employs a shape memoryself-expanding alloy, the anchor alternatively may comprise anelastically or plastically deformable material, e.g., balloonexpandable, or may be a shape memory alloy that responds to temperaturechanges to transition between contracted delivery and expanded deployedstates. The surface finish applied to the material of the anchor may beselected to control the distance, thickness, composition and/or growthpattern of pannus formation, e.g., the external surfaces of the anchormay be electro-polished.

Biocompatible material 56 forming the conduit preferably is resistant tothe transmural and translational ingrowth of pannus material having atissue thickness greater than 0.6 mm. For example, in experimental ePTFEvascular grafts, those with a 60-micron internodal distance showedrapid, transmural infiltration with proliferating smooth muscle cellsand granulation tissue, whereas ePTFE grafts with a 30-micron internodaldistance were observed to develop only a slow growing, thin sheet ofendothelium that advanced only a few millimeters into the graft lumenfrom the adjacent artery. Porous polyester fabric coverings employed onsome atrial septal defect (“ASD”) occlusion devices would be poorchoices for use in the shunt of the present invention, because suchmaterials become completely enmeshed with penetrating fibrotic tissue.It is expected that when shunt 50 comprises an anchor made of, forexample, electro polished nitinol, and biocompatible material 56 may bean inert polymer such as ePTFE with an internodal distance of 30 micronsor less, or is PTFE, such that pannus will grow to a thickness nogreater than about 0.6 mm after extending translationally a distance of3 mm from the site of contact with the Foramen Ovalis (“FO”) tissue. Insuch cases, interior lumen of the conduit is not expected to narrowbeyond a total of 1.2 mm from its original diameter and the neck. Forthe purposes of this patent the term “luminal narrowing” shall bedefined as a loss of minimal shunt lumen diameter of greater than 25%and the term “luminal obstruction” is defined as total (100% loss oflumen diameter) blockage of the lumen to the flow of blood.

Circumferential struts 58 a-58 e and longitudinal struts 57 preferablycomprise a unitary construction, that is, the entire anchor is laser cutfrom a tube of shape memory metal. Biocompatible material 56 maycomprise, for example, a sheet of a polymer such as expandedpolytetrafluoroethylene (“ePTFE”), polytetrafluoroethylene (“PTFE”,)silicone, polycarbonate urethane, DACRON (polyethylene terephthalate),Ultra High Molecular Weight Polyethylene (UHMWPE), or polyurethane. Thebiocompatible material may also be a metal, ceramic, carbon nanotubearray or any other suitable biocompatible material. For example,biocompatible material 56 may comprise ePTFE with an up to 30-microninternodal distance, and may be applied as inner and outer layerssintered together to form a unitary conduit. Alternatively,biocompatible material 56 may be applied to the inner lumen and theoutside of the anchor using electrospinning techniques. Other methods ofencapsulation and other suitable polymers that prevent transmuralingrowth of pannus tissue may alternatively be used, as will beunderstood by one skilled in the art. Bare metal regions of the anchor,and any other regions of the anchor, optionally may be electropolishedor otherwise treated to inhibit thrombus formation using known methods.

Shunt 50 differs from shunt 10 of FIGS. 1A to 1C in that shunt 80 iscurved along central longitudinal axis 81. As illustrated in FIG. 6A,inlet end 52 at the LA entry port in the LA is in a first plane, andoutlet end 55 at the RA exit port in the RA is in a second planedifferent from the first plane, such that the first and second planesintersect at point J. For example, the first and second planes mayintersect an angle between 20 and 45 degrees, e.g., 30 degrees. FIG. 6Aillustrates a first profile of shunt 50 having a first orientation,whereas FIG. 6B illustrates a second profile of shunt 80 having a secondorientation, looking into outlet end 83 of shunt 80. By comparing FIGS.6A and 6B, the second orientation of the second profile of shunt 50 isapproximately 90 degrees from the first orientation of the first profileof shunt 50 when shunt 50 is rotated about central longitudinal axis 59of shunt 50. As shown in FIG. 6A, from the first profile of shunt 50,central longitudinal axis 59 has a curved shape, whereas in FIG. 6B,from the second profile of shunt 50, central longitudinal axis 59 is astraight line. As will be understood by a person ordinarily skilled inthe art, central longitudinal axis 59 may be curved in a manner suchthat no profile of shunt 50 at any orientation depicts centrallongitudinal axis 59 as a straight line, e.g., when central longitudinalaxis 59 has a helical shape.

FIGS. 6C and 6D illustrate shunt 50 from additional views. FIG. 6Eillustrates shunt 50 when implanted in a hole within the atrial septum.As shown in FIG. 6E, neck region 53 of shunt 50 is situated in a passageformed in atrial septum AS, such that inlet end 52 of shunt 50 isdisposed within left atrium LA and outlet end 55 of shunt 50 is disposedwithin right atrium RA of the patient. Accordingly, as blood entersshunt 50 through inlet end 52, blood flow is redirected along thecurvature of central longitudinal axis 59 of shunt 50, and exits shunt50 via outlet end 55 into right atrium RA at a different angle from thedirection of blood flow path through inlet end 52. For example, bloodmay enter inlet end 52 of shunt 50 from within the left atrium LA at anentry angle substantially perpendicular to the atrial septum AS, andexit outlet end 55 of shunt 50 in the right atrium RA at an exit anglerelative to the entry angle that is equivalent to the angle at which thefirst plane intersects the second plane at point J.

Referring now to FIGS. 7A through 7F, an alternative exemplaryembodiment of a shunt constructed in accordance with the principles ofthe present invention is provided. Shunt 60 is constructed similar toshunt 50 of FIGS. 6A to 6E. For example, as illustrated in FIG. 7A,inlet end 62 at first flared end region 61, e.g., the LA entry port inthe LA, is in a first plane, and outlet end 65 at second flared endregion 64, e.g., the RA exit port in the RA, is in a second planedifferent from the first plane, such that the first and second planesintersect at point K. For example, the first and second planes mayintersect an angle between 20 and 45 degrees, e.g., 30 degrees. Shunt 60may, for example, be formed of a metal frame and encapsulated with abiocompatible material. FIG. 7A illustrates a first profile of shunt 60having a first orientation, whereas FIG. 7B illustrates a second profileof shunt 60 having a second orientation, looking into outlet end 65 ofshunt 60. By comparing FIGS. 7A and 7B, the second orientation of thesecond profile of shunt 60 is approximately 90 degrees from the firstorientation of the first profile of shunt 60 when shunt 60 is rotatedabout central longitudinal axis 69 of shunt 60. As shown in FIG. 7A,from the first profile of shunt 60, central longitudinal axis 69 has acurved shape, whereas in FIG. 7B, from the second profile of shunt 60,central longitudinal axis 69 is a straight line. As will be understoodby a person ordinarily skilled in the art, central longitudinal axis 69may be curved in a manner such that no profile of shunt 60 at anyorientation depicts central longitudinal axis 69 as a straight line,e.g., when central longitudinal axis 69 has a helical shape.

Shunt 60 differs from shunt 50 in that inlet end 62 at the LA entry portin the LA has a cross-sectional shape different from the cross-sectionalshape of outlet end 65 at the RA exit port in the RA. As illustrated inFIG. 7B, outlet end 65 of shunt 60 has a cross-sectional shape having afirst pair of opposing sides that extend parallel and a second pair ofopposing ends that curve. For example, the cross-sectional shape ofoutlet end 65 has two rounded ends 70 and 71, opposite from one another,and two flattened portions 72 and 73, opposite from one another.Alternatively, the cross-sectional shape of outlet end 65 of shunt 60may be an ellipse or an oval. In addition, as illustrated in FIG. 7C,inlet end 62 of shunt 60 has a cross-sectional shape of a circle. Asfurther illustrated in FIGS. 7A and 7B, central longitudinal axis 69 ofshunt 60 may be curved such that rounded end 70 of outlet end 65 isclosest in proximity to inlet end 62. As will be understood by a personordinarily skilled in the art, central longitudinal axis 69 of shunt 60may be curved such that rounded end 71 of outlet end 65 is closest inproximity to inlet end 62. The width of outlet end 65, e.g., thedistance between rounded ends 70 and 71, may be equal to the diameter ofthe cross-sectional shape of circular inlet end 62. Therefore, outletend 65 may have a cross-sectional area that is less than thecross-sectional area of circular inlet end 62, and thus, as will beunderstood by a person ordinarily skilled in the art, blood may exitoutlet end 65 at a faster rate than blood entering shunt 60 via inletend 62. In accordance with another aspect of the present invention, thewidth of outlet end 65 may be larger than or less than the diameter ofthe cross-sectional shape of circular inlet end 62, such that a desiredblood flow rate at outlet end 65 may be achieved.

FIGS. 7D and 7E illustrate shunt 60 from additional views at differentorientations. FIG. 7F illustrates shunt 60 when implanted in a holewithin the atrial septum. As shown in FIG. 7F, neck region 63 of shunt60 is situated in a passage formed in atrial septum AS, such that inletend 62 of shunt 60 is disposed within left atrium LA and outlet end 65of shunt 60 is disposed within right atrium RA of the patient.Accordingly, as blood enters shunt 60 through inlet end 62, blood flowis redirected along the curvature of central longitudinal axis 69 ofshunt 60, and exits shunt 60 via outlet end 65 into right atrium RA at adifferent angle from the direction of blood flow path through inlet end62, and optionally at a faster rate than blood flow entry through inletend 62. For example, blood may enter inlet end 62 of shunt 60 fromwithin the left atrium LA at an entry angle substantially perpendicularto the atrial septum AS, and exit outlet end 65 of shunt 60 in the rightatrium RA at an exit angle relative to the entry angle that isequivalent to the angle at which the first plane intersects the secondplane at point K.

Referring now to FIGS. 8A through 8E, an alternative exemplaryembodiment of a shunt constructed in accordance with the principles ofthe present invention is provided. Shunt 80 is constructed similar toshunt 60 of FIGS. 7A to 7F. For example, as illustrated in FIG. 8A,inlet end 82 at first flared end region 81, e.g., the LA entry port inthe LA, is in a first plane, and outlet end 85 at second flared endregion 84, e.g., the RA exit port in the RA, is in a second planedifferent from the first plane, such that the first and second planesintersect at point L. For example, the first and second planes mayintersect an angle between 20 and 45 degrees, e.g., 30 degrees. Shunt 80may, for example, be formed of a metal frame and encapsulated with abiocompatible material. FIG. 8A illustrates a first profile of shunt 80having a first orientation, whereas FIG. 8B illustrates a second profileof shunt 80 having a second orientation, looking into outlet end 85 ofshunt 80. By comparing FIGS. 8A and 8B, the second orientation of thesecond profile of shunt 80 is approximately 90 degrees from the firstorientation of the first profile of shunt 80 when shunt 80 is rotatedabout central longitudinal axis 89 of shunt 80. As shown in FIG. 8A,from the first profile of shunt 80, central longitudinal axis 89 has acurved shape, whereas in FIG. 8B, from the second profile of shunt 80,central longitudinal axis 89 is a straight line. As will be understoodby a person ordinarily skilled in the art, central longitudinal axis 89may be curved in a manner such that no profile of shunt 80 at anyorientation depicts central longitudinal axis 89 as a straight line,e.g., when central longitudinal axis 89 has a helical shape.

In addition, like shunt 60 of FIGS. 7A to 7F, outlet end 85 of shunt 80has a cross-sectional shape having a first pair of opposing sides thatextend parallel and a second pair of opposing ends that curve. Forexample, the cross-sectional shape of outlet end 85 has two rounded ends90 and 91, opposite from one another, and two flattened portions 92 and93, opposite from one another. Alternatively, the cross-sectional shapeof outlet end 85 of shunt 80 may be an ellipse or an oval. Shunt 80differs from shunt 60 in that central longitudinal axis 89 of shunt 80is curved such that flattened portion 92 of outlet end 85 is closest inproximity to inlet end 82. As will be understood by a person ordinarilyskilled in the art, central longitudinal axis 89 of shunt 80 may becurved such that flattened portion 93 of outlet end 85 is closest inproximity to inlet end 82.

FIGS. 8C and 8D illustrate shunt 80 from additional views at differentorientations. FIG. 8E illustrates shunt 80 when implanted in a holewithin the atrial septum. As shown in FIG. 8E, neck region 83 of shunt80 is situated in a passage formed in atrial septum AS, such that inletend 82 of shunt 80 is disposed within left atrium LA and outlet end 85of shunt 80 is disposed within right atrium RA of the patient.Accordingly, as blood enters shunt 80 through inlet end 82, blood flowis redirected along the curvature of central longitudinal axis 89 ofshunt 80, and exits shunt 80 via outlet end 85 into right atrium RA at adifferent angle from the direction of blood flow path through inlet end82, and optionally at a faster rate than blood flow entry through inletend 82. For example, blood may enter inlet end 82 of shunt 80 fromwithin the left atrium LA at an entry angle substantially perpendicularto the atrial septum AS, and exit outlet end 85 of shunt 80 in the rightatrium RA at an exit angle relative to the entry angle that isequivalent to the angle at which the first plane intersects the secondplane at point L.

Referring now to FIGS. 9A through 9E, an alternative exemplaryembodiment of a shunt constructed in accordance with the principles ofthe present invention is provided. Shunt 100 is constructed similar toshunt 10 of FIGS. 1A to 1C, except that inlet end 102 at first flaredend region 101, e.g., the LA entry port in the LA, has a cross-sectionalshape different from the cross-sectional shape of outlet end 105 atsecond flared end region 104, e.g., the RA exit port in the RA. Shunt100 may, for example, be formed of a metal frame and encapsulated with abiocompatible material.

FIG. 9B illustrates shunt 100 from a profile having an orientation whereshunt 100 of FIG. 9A is rotated 90 degrees about the horizontal dottedline. Thus, rounded ends 110 and 111 of outlet end 105 are depicted asopposing ends of outlet end 105 in FIG. 9B. As illustrated in FIG. 9B,inlet end 102 of shunt 100 has a cross-sectional shape of a circle, andoutlet end 105 of shunt 100 has a cross-sectional shape having a firstpair of opposing sides that extend parallel and a second pair ofopposing ends that curve. For example, the cross-sectional shape ofoutlet end 105 has two rounded ends 110 and 111, opposite from oneanother, and two flattened portions 112 and 113, opposite from oneanother. Alternatively, the cross-sectional shape of outlet end 105 ofshunt 100 may be an ellipse or an oval.

As shown in FIG. 9B, the width of outlet end 105, e.g., the distancebetween rounded ends 110 and 111, may be approximately equal to thediameter of the cross-sectional shape of circular inlet end 102.Therefore, outlet end 105 may have a cross-sectional area that is lessthan the cross-sectional area of circular inlet end 102, and thus, aswill be understood by a person ordinarily skilled in the art of fluidmechanics, blood may exit outlet end 105 at a faster rate than bloodentering shunt 100 via inlet end 102. In accordance with another aspectof the present invention, the width of outlet end 105 may be larger thanor less than the diameter of the cross-sectional shape of circular inletend 102, such that a desired blood flow rate at outlet end 105 may beachieved.

FIG. 9C illustrates shunt 100 from a profile having an orientation whereshunt 100 of FIG. 9A is rotated 90 degrees about central longitudinalaxis 109. Thus, flattened portions 112 and 113 of outlet end 105 aredepicted as opposing ends of outlet end 105 in FIG. 9C. FIG. 9Dillustrates shunt 100 from an additional view. FIG. 9E illustrates shunt100 when implanted with respect to the atrial septum. As shown in FIG.9E, neck region 103 of shunt 100 is situated in a passage formed inatrial septum AS, such that inlet end 102 of shunt 100 is disposedwithin left atrium LA and outlet end 105 of shunt 100 is disposed withinright atrium RA of the patient. Accordingly, blood enters shunt 100through inlet end 102, and exits shunt 100 via outlet end 105 into rightatrium RA at faster rate than blood flow entry through inlet end 102.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

While various illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made herein without departing from theinvention.

What is claimed:
 1. A method for regulating blood volume distributionacross an atrial septum, the method comprising: advancing an asymmetricdevice in a contracted state toward the atrial septum, the asymmetricdevice comprising a first expandable end region, a second expandable endregion, and a neck region disposed therebetween; expanding the firstexpandable end region from the contracted state to an expanded state ina first atrium such that a first end of the first expandable end regionis in a first plane; and expanding the second expandable end region fromthe contracted stated to the expanded state in a second atrium such thata second end of the second expandable end region is in a second plane,wherein the first plane and the second plane intersect, and wherein theneck region is implanted at the atrial septum.
 2. The method of claim 1,further comprising permitting blood to flow through the asymmetricdevice via a conduit defining a passageway therethrough.
 3. The methodof claim 2, wherein permitting blood to flow comprises permitting highvelocity flow through the passageway of the conduit while limitingparadoxical emboli passing across the passageway during a transientpressure gradient reversal.
 4. The method of claim 2, wherein theconduit comprises a layer of biocompatible material.
 5. The method ofclaim 1, wherein the first plane intersects the second plane at an anglebetween 20 and 45 degrees.
 6. The method of claim 1, wherein expandingthe first expandable end region comprises positioning the first end ofthe first expandable end region such that it extends at least 3 mm intothe first atrium.
 7. The method of claim 1, wherein expanding the secondexpandable end region comprises positioning the second end of the secondexpandable end region such that it extends at least 3 mm into the secondatrium.
 8. The method of claim 1, wherein the first expandable endregion, in the expanded deployed state, forms a filter that preventsemboli from entering the second end of the second expandable end region.9. The method of claim 1, wherein the asymmetric device comprises aplurality of longitudinal struts interconnected by a plurality ofcircumferential sinusoidal struts.
 10. The method of claim 1, wherein aninner diameter in the neck region is in a range of 5 mm to 6.5 mm. 11.The method of claim 1, wherein the inlet end of the first expandable endregion has a first cross-sectional shape, and wherein the outlet end ofthe second expandable end region has a second cross-sectional shapedifferent from the first cross-sectional shape of the inlet end of thefirst expandable end region in the expanded state.
 12. The method ofclaim 11, wherein the first cross-sectional shape of the inlet end offirst expandable end region in the expanded state is a circle.
 13. Themethod of claim 12, wherein the second cross-sectional shape of theoutlet end of the second expandable end region in the expanded state hasa first pair of opposing sides that extend parallel and a second pair ofopposing ends that curve.
 14. A method for regulating blood volumedistribution across an atrial septum, the method comprising: advancingan asymmetric device in a contracted state toward the atrial septum, theasymmetric device comprising a first expandable end region, a secondexpandable end region, and a neck region disposed therebetween;expanding the first expandable end region from the contracted state toan expanded state in a first atrium such that a first end of the firstexpandable end region expands to a circular cross-sectional shape; andexpanding the second expandable end region from the contracted state tothe expanded state in a second atrium such that a second end of thesecond expandable end region expands to a cross-sectional shape having afirst pair of opposing sides that extend parallel and a second pair ofopposing ends that curve and the neck region is implanted at the atrialseptum.
 15. The method of claim 14, further comprising permitting bloodto flow through the asymmetric device via a conduit defining apassageway therethrough.
 16. The method of claim 14, wherein the firstend has a cross-sectional area greater than a cross-sectional area ofthe second end.
 17. The method of claim 16, wherein the first endpermits blood to enter at a first rate and the second end permits bloodto exit at a second rate, the second rate faster than the first rate.18. The method of claim 14, wherein the inlet end of the firstexpandable end region in the expanded state is in a first plane, and theoutlet end of the second expandable end region in the expanded state isin a second plane, and wherein the first plane intersects the secondplane.
 19. The method of claim 14, further comprising a centrallongitudinal axis, wherein from a first profile of the device having afirst orientation, the central longitudinal axis has a curved shape. 20.The method of claim 19, wherein at the second orientation of the secondprofile of the device, one of the first pair of opposing sides thatextend parallel of the cross-sectional shape of the second expandableend region in the expanded state is closest to the first expandable endregion.